PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Immunol. Author manuscript; available in PMC 2010 August 15.
Published in final edited form as:
PMCID: PMC2766168
NIHMSID: NIHMS128695

Secondary Lymphoid Organs: Responding to Genetic and Environmental Cues in Ontogeny and the Immune Response1

Abstract

Secondary lymphoid organs (SLOs) include lymph nodes (LNs), spleen, Peyer’s patches (PPs) and mucosal tissues- the nasal associated lymphoid tissue (NALT), adenoids, and tonsils. Less discretely anatomically defined cellular accumulations include the bronchus associated lymphoid tissue (BALT), cryptopatches, and isolated lymphoid follicles (ILFs). All SLOs serve to generate immune responses and tolerance. SLO development depends on the precisely regulated expression of cooperating lymphoid chemokines and cytokines LTα, LTβ, RANKL, TNF, IL-7, and perhaps IL-17. The relative importance of these factors varies between the individual lymphoid organs. Participating in the process are lymphoid tissue initiator (ltin), lymphoid tissue inducer (ltind), and lymphoid tissue organizer (lto) cells. These cells, and others that produce the crucial cytokines, maintain SLOs in the adult. Similar signals regulate the transition from inflammation to ectopic or tertiary lymphoid tissues (TLOs).

The mammalian immune system, a cooperative endeavor between the innate and acquired arms, provides an optimal environment for defense against the invasion of pathogens at any site in the body. The sites of organized lymphoid cell accumulations are termed primary and secondary lymphoid organs (SLOs)3. Diverse populations of functionally mature, but naïve, lymphocytes are generated in the absence of foreign antigens in the primary lymphoid organs (thymus, fetal liver, bone marrow). These cells seed the SLOs to optimally respond to foreign invaders.

Here, we review the structure, function, development and maintenance of SLOs where T and B cells encounter antigen to generate effector cells or tolerance. SLOs include the spleen, lymph nodes (LNs), Peyer’s patches (PPs), tonsils and adenoids, and, in the mouse, rat, and rabbit, the nasal associated lymphoid tissue (NALT). During antigenic challenge, additional lymphoid tissues are apparent in the lung (bronchus associated lymphoid tissues (BALT)) and intestine (isolated lymphoid follicles (ILFs)). The blood vessels of SLOs allow antigen access. LNs, which are also served by lymphatic vessels, are effective in mounting responses to antigens that are present in tissues. These antigens originate from foreign invaders that are transported by antigen presenting cells or are derived from self-antigens. The capacity to discriminate between dangerous foreign antigens and benign self-antigens relies on the antigen presenting cells and their state of activation and the recognition capacity of the naïve T and B cells. DCs constitutively sample self-antigens and migrate to draining LNs even in the steady state. Because most self-antigen bearing DCs in LNs are immature, they do not effectively activate naïve cells. They regulate self-reactive T cells by inducing anergy, clonal deletion, and/or expanding regulatory T cells (1).

Tertiary lymphoid organs (TLOs), or more accurately, tertiary lymphoid tissues, are accumulations of lymphoid cells that arise in the adult. These ectopic lymphoid accumulations respond to environmental stimuli with chronic inflammation during microbial infection, graft rejection, or autoimmune disease. They are classified as lymphoid tissues because they resemble SLOs with regard to cellular composition and compartmentalization, chemokines, vasculature and function (2).

Organization of SLOs

Individual SLOs are similarly organized, though their vasculature, mode of antigen entrance, local environment, and stimuli to which they are subjected may differ. All SLOs include B and T cells, antigen presenting cells, stromal cells, and a vascular supply. We summarize similarities and differences in these organs as they impact upon our discussion of their developmental signals.

LNs are located at vascular junctions and are served by lymphatic vessels that deliver antigen and antigen presenting cells. A capsule derived from lymphatic vessels surrounds the highly compartmentalized LN (Fig. 1A). The collected lymph and cell contents enter the LN via several afferent lymphatic vessels and filter through the node through the lymphatic sinuses in the medulla(3). Factors from afferent lymph can be either transported deep into the LN cortex or move via the subcapsular sinus and leave through efferent lymphatic vessels (4). Cells and antigen also enter the LN via an arteriole, which branches into a capillary bed. The post capillary venules called high endothelial venules (HEVs) have a distinctive appearance with a plump cuboidal endothelium. The adhesion molecules that slow the flow of naïve lymphocytes include peripheral node addressin (PNAd) and mucosal associated adhesion molecule (MAdCAM-1). MAdCAM-1, the ligand for the integrin α4β7, is only apparent in early development on HEVs of peripheral LNs (PLNs). PNAd, the ligand for L-selectin replaces MAdCAM-1 after birth in mouse peripheral LNs (5). MAdCAM-1 remains along with PNAd in mucosal LNs (MLNs).

Figure 1
The basic organization of SLOs is similar. A. Lymph node. The lymph node is divided into an outer cortex and inner medulla surrounded by a capsule and lymphatic sinus. The cortex includes B cells and follicular dendritic cells. The paracortical region ...

Lymphoid chemokines, CCL19 (ELC) and CCL21 (SLC), expressed on the HEVs (6), induce changes in the affinity of LFA-1 on lymphocytes, allowing their interaction with ICAM-1 on the HEVs, and then transmigration of T cells to the paracortical region. Both T cells and DCs are attracted to the paracortical region by their expression of CCR7, the receptor for CCL19 and CCL21. CXCL13 (BLC), produced by stromal cells in the B cell follicles, attracts CXCR5 expressing B cells (7). The cortical region consists of primary follicles of densely packed naïve B cells and follicular dendritic cells (FDCs). Antigen activated B cells proliferate, and secondary follicles and germinal centers develop. Plasma cells are concentrated in the medulla as they prepare to leave the LN and circulate to the bone marrow. A network composed of reticular fibers, fibrous extracellular matrix bundles and fibroblastic reticular cells supports the entire LN (4). After naïve T and B cells encounter antigen, they undergo extensive changes in expression of chemokine receptors and adhesion molecules that result in their movement to different areas of the LN or leaving it all together. A conduit system physically connects the lymphatic sinus with the walls of blood vessels and enables incoming factor(s) from lymph to move into the paracortical area (4, 8, 9).

Mucosal associated lymphoid tissues (MALT), which quantitatively include the vast majority of lymphoid cells in the body are major producers of secreted IgA and are responsible for inducing and maintaining tolerance to food antigens and commensal bacteria (10). Though the structures and locations of some MALTs are predetermined, all are somewhat plastic and prone to induction and remodeling due to their constant exposure to environmental antigens. The tonsils and adenoids in humans and NALT in rodents are in fixed locations. So are PPs, but their number varies by species and antigen exposure. The BALT and ILFs are located in predetermined sites: the lung and the small intestine but are even more plastic and subject to environmental influences. PPs, tonsils, adenoids, and NALT exhibit the same basic organization as LNs with compartmentalized T and B areas, antigen presenting cells, lymphoid chemokines, HEVs and lymphatic vessels (Fig. 1B). M cells, specialized antigen presenting cells, also serve the NALT, PPs, and BALT. HEV vascular addressins differ between MALTs and LNs and between individual MALTs. PP HEVs express MAdCAM-1, but very low, or undetectable, PNAd. NALT HEVs express PNAd (11). The BALT is less organized, but more environmentally regulated than PPs or NALT. There is debate concerning whether BALTs should be considered as SLOs or as TLOs since they are are not present in all species, and are nearly entirely dependent on antigenic stimulation or age. Nevertheless, when they are present, they exhibit organization similar to PPs, with T and B cell compartments and M cells. Their HEVs differ in that they express PNAd rather than MAdCAM-1 and high levels of VCAM-1 (12). Cryptopatches, composed of linc-kit+ cells, DCs, and VCAM-1+ stromal cells (13) with few or no mature T and B cells, give rise to isolated lymphoid follicles ILFs (14, 15) which include B and T cells, resemble primitive LNs, and are found in the colon and small intestine.

The spleen is divided into two anatomically and functionally distinct areas: red pulp and white pulp. The red pulp, in its activities as a hematogenous organ, removes damaged cells, and acts as a site for iron storage and turn over. The white pulp is an organized lymphoid structure. The spleen is highly vascularized, but has no HEVs or afferent lymphatic vessels. Rather, the splenic artery, located immediately below the capsule is the source of cells and antigens. The marginal sinus and marginal zone demarcate the red and white pulp. The MZ, which surrounds the white pulp, represents a important transition between the innate and acquired immune systems; it is the first region after the red pulp encountered by blood borne antigens and is richly supplied with specialized phagocytic cells: the MZ macrophages and MZ metallophilic macrophages. The MZ also contains a specialized subset of B cells that differ phenotypically and functionally from follicular B cells and are considered a bridge between the innate and adaptive immune systems. The organization of the remainder of the white pulp of the spleen is similar to that of the LN, compartmentalized into B and T cell areas with the same lymphoid chemokines that are found in LNs and PPs. The white pulp consists of a central arteriole surrounded by T cells, the periarteriolar lymphoid sheath, that is surrounded by B cells. As in the LN, T cells interact with DC, B cells migrate to the follicles where they interact with FDCs, and T cells interact with B cells at the border of the T and B cell areas, giving rise to germinal centers.

Cytokines, chemokines, signaling molecules, and transcription factors in lymphoid organogenesis

Insight into lymphoid organ development has come from analyses of mice deficient in particular genes, transgenic for lymphoid chemokines or cytokines, or after treatment(2) with cytokine inhibitors. The action of multiple transcription factors, cells, cytokines, chemokines and signaling molecules is critical for the development of a fully functional lymphoid system. The results of deletion of individual cytokines, chemokines, and transcription factors have been catalogued in several recent reviews (1618); the reader is referred to tables in these publications. Here, we emphasize the importance of cooperating chemokines and cytokines in individual SLOs. Lymphotoxin (LTα, TNFβ) was initially described (19, 20) as a cytotoxic factor made by activated “lymphocytes” (T cells) that correlated positively with delayed type hypersensitivity (21). LT is also crucial for lymphoid organ development. Secreted LTα3, signaling through TNFRI p55, and membrane bound LTα1β2, signaling through LTβ receptor (LTβR) and TRAF 6, are absolutely crucial for SLO development. Lta−/− mice lack all LNs and PPs and exhibit a severely disorganized NALT (11, 2224). Their splenic defects a disorganized white pulp with loss of T and B cell compartmentalization, loss of MZ macrophages, metallophilic macrophages, MZ B cells, MAdCAM-1 sinus lining cells, and germinal centers. Ltβ−/− mice lack PLNs but retain mesenteric, sacral and cervical LNs (2527). Splenic disorganization of Ltb−/− mice is somewhat less pronounced than that of Lta−/− mice. The phenotype of Ltbr−/− mice is similar to that of Lta−/− mice (28). LIGHT (lymphotoxin-related inducible ligand) is also recognized by the LTβR, but no defect in lymphoid organ development is observed in Light−/− mice (29). However, mice doubly deficient in LIGHT and LTβ have fewer mesenteric LNs than those deficient in LTβ alone, suggesting an additive effect of the two LTβR ligands. Treatment of pregnant mice with LTβR-Ig inhibits most LNs in the developing embryos, depending on the time of administration. However, mesenteric LNs are not inhibited by this treatment. These studies indicate that individual LNs differ in their kinetics and cytokine requirements during ontogeny (30). TNFα participates in lymphoid organ development, though its role is not as crucial as that of LT. Tnfa−/− mice lack those splenic populations that are also absent in Lta−/− mice (31); some reports indicate that they also lack PPs (32). Tnfr1−/− mice show splenic, but not LN defects, similar to those of Lta−/− mice with the exception of MZ B cells and they do not give rise to mature ILFs (14). Cooperation between the various cytokines is evident from studies of mice doubly deficient in LTβR and TNFRp55. These mice lack MLNs and exhibit more severe splenic defects than do Ltb−/− mice (33), suggesting that LTα3 signaling through TNFRp55 is necessary for MLN. Similarly, evidence for cooperation between LTαβ and TNF in splenic organization is apparent from studies of mice doubly deficient in LTβ and TNF (33).

RANKL, another member of the larger TNF family, also participates in LN development. Mice deficient in RANK (also called TRANCER or OPG) (34) or RANKL (also called TRANCE or OPGL) (35, 36) exhibit defects in LNs but not PPs. Mice deficient in the common γ chain of several cytokine receptors, including IL-7, lack LNs (37), and Il7ra−/− mice lack PPs (38) and some LNs (39). Thus, the statement that IL7, signaling through the IL7R and JAK3 kinase is required for PP but not LN development (40) is incorrect, since Jak3−/− mice lack both PLNs (41) and PPs (38). LNs of Il7r−/− mice are poorly populated (42), indicating that IL7 is crucial for their maintenance. Furthermore, transgenic over expression of IL7 directed by a Class II Eα promoter resulted not only in increased numbers of PPs, but also in the generation of additional LNs (43).

CXCR5 or CXCL13 deficient mice(44, 45) lack some LNs and almost all PPs (44, 45). Mice doubly deficient in CXCL13 and IL7Rα lack all LNs, including MLNs, indicating cooperation between these factors (39). Paucity of lymph node T (plt/plt) mice lack CCL19 and CCL21, but retain LNs and PPs, though they do exhibit defects in T cell homing and NALT maturation (46).

Transcription factors crucial for lymphoid organogenesis include helix-loop-helix transcription factor inhibitor (Id2) (47) and retinoid acid-related orphan receptors (RORs) RORγ and RORγt (48, 49). Mice that lack RORγt lack LNs and PPs (48), though their NALTs are normal in size and cellularity (24). Factors that uniquely affect splenic development include homeobox genes and transcription factors that are expressed in the spleno-pancreatic mesenchyme at E10.5; for example Hox11 mice are asplenic (summarized in (50)). Both the canonical and alternative NF-κB signaling pathways contribute to SLO development (51). The alternative pathway, characterized by the NF-κB-inducing kinase (NIK) and IKKα is particularly important. aly/aly mice, which have a point mutation in Nik, lack all LNs and PPs (52, 53). Mice with a mutated form of the Ikka gene have defective HEVS, further confirming that the LTβR signal regulates HEVs and lymphoid chemokines through the alternative NFκB pathway (54).

Cooperation is necessary between several cell types and vascular systems to generate SLOs

Lymphatic vessels are crucial components of the immune system and contribute to SLO development. The generation of embryonic lymphatic vessels from preexisting veins in pig embryos was first described in the early 1900s and has recently been molecularly defined (summarized in (55). At mouse E9, Sox18, a homeobox gene product is expressed in several cell types including a subpopulation of endothelial cells in the cardinal vein {Francois, 2008 #55). At E.9.75 it directly activates Prox1, which is crucial for maintenance of the lymphatic phenotype (56). LYVE-1 is also expressed at this time in those lymphatic-biased polarized endothelial cells. Prox1 induces expression of a variety of genes, including intergrin α9 and VEGFR-3, allowing migration towards VEGF-C (57). LYVE-1+ Prox1+ VEGFR-3+ endothelial cells are committed towards a lymphatic pathway. Their further separation from venous endothelium requires a Syk/SLP-76 signal (summarized in (55)).

Histologic studies in the rat revealed that popliteal and inguinal LN anlagen originally appear in a limited mesenchymal area along the vein wall at E17. The next day, lymphatic vessels form a sac, running parallel to the vein. The LN anlage develops into a bulb-shaped structure with lymphatic vessels and the subcapsular sinus originating from the remaining lymphatic vessel. At the next stage, the LN divides into a primitive cortex, the basic network of reticular cells and medulla and lymphocytes scatter in the LN anlage. Blood vessels branch into the LN and later develop into HEVs (58). The primary follicles appear at day 18 after birth, indicating B cell migration into LNs is a late event during lymphoid organogenesis Studies in the mouse confirm and extend these observations (summarized in (18)).

Nishikawa and colleagues, based on their studies of PP development, articulated the concept that lymphoid organ development involves interactions between distinct cell types in several steps (59). The first step is the development of VCAM-1+ ICAM-1+MAdCAM-1+ “organizing clusters”; the second, accumulation of cells expressing IL7R and CD4; the third, lymphocytes expressing CD3 or B220. The current model, which supports this concept, postulates interactions between initiator cells, inducer cells, and organizer cells. The various abbreviations for these cells have included: LTin (lymphoid tissue initiator), LTi (lymphoid tissue inducer) and LTo (lymphoid tissue organizer) (18). Somewhat confusingly, LT in that terminology is an abbreviation for lymphoid tissue, not lymphotoxin. These cells have also been called: PPin (Peyer’s patches initiator), PPi (PP inducer), and PPo (PP organizer) or LNi (lymph node inducer) and LNo (lymph node organizer) (42). To reduce confusion between lymphoid tissue and lymphotoxin, and to emphasize the common mechanisms used in all SLOs, we call these cells ltini (lymphoid tissue initiator), ltind (lymphoid tissue inducer), and lto (lymphoid tissue organizer) cells. Though the relative importance of particular factors produced by these cells differs in individual lymphoid organs, the general scheme is similar. It has become clear that the development of a fully functional immune system involves cooperation not only between multiple cell types, but also between multiple cytokines, chemokines, and their receptors.

The ltini cells have not been as extensively characterized as the ltind and lto cells, though, at least in PPs, ltini cells are CD11c positive (59). Such CD45+CD4CD3IL7RCDllc+ cells in the mouse embryonic gut and adult spleen express RET, a tyrosine kinase receptor previously described as a neuroregulator. Since mice deficient in RET lack PPs (60) Mesenchymal-derived PP lto cells produce artremin, a RET ligand (60), suggesting an interaction between ltini cells and lto cells in PP development. The role of RET in other SLOs has not been investigated.

Lto cells attract, activate, and respond to CD4+CD3CD45+ ltind cells, which are derived from fetal liver progenitors (17, 49, 61, 62). These ltind cells are dependent on id2 (47) and RORγt (48), express the integrin a4b7, (62) interact with VCAM-1 on resident lto cells and accumulate in the developing LN or PP, forming clusters with lto cells to initiate a cascade of intracellular and intercellular events. that lead to the maturation of the primordial SLOs. Although initiation of the LN anlagen is LT independent, maintenance of lto cells is dependent on LTα (63). During this early step, depending on the organ, a positive feedback loop involves several signaling pathways between IL7, CXCL13, LTβR, and TNFR expressed by lto cells and IL7Rα, CXCR5, LTαβ, LTα, and TNFα by ltind cells. At least two lto cell populations have been described. The proportion of cells that express high levels of VCAM, ICAM-1, and MAdCAM-1, compared to intermediate levels of those adhesion molecules varies between neonatal MLNs and PLNs (64), providing further evidence of the somewhat subtle, but none the less real, differences in the regulation of these different LNs. Heterogeneity is also apparent in the expression levels of a variety of genes of the presumptive mesenteric LN lto cells compared to those from developing PPs (65). For example, although lto cells in both sites express RANKL, the levels differ, suggesting that the environment influences the relative importance of particular cytokines in individual organs in the course of development. Cryptopatch cells have some characteristics of other ltind cells in that they express RORγt and IL-7R; but they also express CCR6, and ILF development is dependent on IL-7, CCR6 and its receptor CCL20 (66).

Although, RANK and RANKL are required for LN development, there has been some confusion regarding the identity of ligand producers and responders. RANKL appears to be produced by both lti and lto cells. RANKL expression has been noted in lto stromal cells (40, 65, 67, 68), in ltind cells (35, 69, 70) and in both cell types(71). At least one publication describes production of both RANK and RANKL by ltind cells (35). It is likely that the activity of this ligand- receptor pair is both autocrine and paracrine. Rossi et al showed that RANKL production by thymic CD4+CD3 cells affects stromal cells (70), whereas Yoshida et al indicate that RANKL stimulates ltind cells to produce a factor that binds LTβR (presumably LTαβ), suggesting that ltind cells express the receptor (RANK) (40). Thus, the effect may be dependent on the microenvironment and developmental window of individual SLOs. As noted above, the relative importance of IL-7 for individual SLOs varies. IL7/IL7R signaling results in an increased number of CD4+CD3 cells in the PPs indicating that this cytokine is necessary for the maintenance of ltind cells in that organ. However, other data suggest that the ltind cells for PP and LNs are essentially similar; IL7 administration to Traf-6−/− LN-deficient embryos restores those organs (40). Initiation of NALT organogenesis occurs in the absence of IL-7R, LTβR, LTα and NIK (24, 72), but is dependent on CD3CD4+CD45+ cells (72). However, LTα3 and LTα1β2 are both crucial for postnatal NALT development with regard to expression of lymphoid chemokines, HEV development and response to antigen (11). The relative importance of the various cytokines in individual SLOs is illustrated in Figure 2.

Figure 2
The general developmental program is similar between different SLOs, but the importance of individual factors varies. CD4+CD3CD45+α4β7+ ltind cells interact with VCAM+ICAM-1+MAdCAM-1+ mesenchymal lto cells. Those factors crucial ...

The prolonged interaction between ltind and lto cells promotes the development of HEVs. PNAd replaces MAdCAM-1 in the first few days in PLNs (5). LTα alone can induce MAdCAM-1, but PNAd requires LTαβ. In the remaining MLNs of Ltb−/− mice, PNAd expression is impaired indicating that optimal LN HEV PNAd expression requires LTα1β2 signaling through the LTβR and the alternative NFκB pathway (54, 73, 74). Since the maturation of HEVs is coincident with further development of the LN (5), the homing of LTαβ expressing lymphocytes most likely also contributes to HEV maturation. NALT HEVs develop after birth and are regulated in a fashion similar to those of LNs, with LTαβ playing a crucial role in PNAd and the sulfotransferase that contributes to that functional addressin (11). Though an extensive literature exists on the development of lymphatic vessels from cardinal veins (55), less is known regarding their regulation in ontogeny in LNs. The roles of ltind and lto cells in this regard have not been extensively analyzed, though a recent publication indicates that even the defective LN anlagen in Lta−/− mice have LYVE-1+ vessels but no capsule(71)

Th17 cells that express IL17A and IL17F, IL-22, and IL-21 are implicated in several models of autoimmunity (summarized in (75)). These cells have not previously been implicated in lymphoid organogenesis. However, the recent revelations that ltind cells and Th17 cells share (at least one) cytokine and transcription factor buttress the concept that SLOs and TLOs represent the end products of similar mechanisms. RORyt, which as noted above is required for the development of most SLOs, is also crucial for differentiation of Th17 cells (76).. Recent reports indicating that cells with the phenotypic characteristics of ltind cells in adult spleen (77) and human fetal lymphoid tissue (78) produce IL17 further blur the difference between these cells and raise the intriguing possibility that this cytokine could contribute to SLO development. Although no abnormalities were reported in the cell populations of spleens, LNs, and thymi of Il17a−/− (79) orIl17a−/−Il17f−/− mice (80), these organs were not analyzed histologically, leaving open the possibility that IL17 could contribute to the microarchitecture or maintenance of SLOs.

Maintenance of lymphoid organs

SLOs, located in anatomically distinct sites, were formerly considered as static structures. Our thinking regarding this issue has evolved to an appreciation of the dynamism of lymphoid organs and the realization that SLOs are quite plastic and are influenced by their environments. HEV maturation, evident as a change from MAdCAM-1hi HEC6STlo to PNAdhi HEC6SThi (5), is coincident with the entrance of lymphocytes after birth, indicating that the mature HEV phenotype relies on the LN microenvironment (5, 58). Furthermore, interruption of lymphatic vessel flow drastically affects HEVs, reverting them to an immature phenotype (summarized in (81). Stromal cells with characteristics of lto cells have been described in mature LNs (67). CD45+CD4+CD3 ltind cells are rare in adult SLOs (82), though they have been noted in adult spleens where they may contribute to generation of memory (83). Furthermore, LT-producing cells in addition to ltind cells, such as T, B, and NK cells presumably serve to maintain adult LNs. LTβR-Ig treatment of adult mice results in altered LNs, with changes in cellular composition, HEV reversion to an immature state, inhibited FDC function, and disrupted immune responses to foreign antigens (81, 84, 85). Thus, in addition to its critical role in lymphoid organogenesis, LTβR is essential for maintaining LN function. The similarities between cells that induce inflammation (Th17) and those that induce lymphoid organs (ltind) add additional support to the notion that SLOs and TLOs share developmental programs and functions.

The most plastic, environmentally regulated lymphoid tissues are in the adult gut. The number and cellularity of PPs increase after immunization and decrease with aging (2, 86). After mice are exposed to microbes or during some forms of autoimmunity, cryptopatches give rise to ILFs (14, 49) and may even recapitulate the ontogenic program in response to these stimuli (87).

The spleen responds to its environment with changes in cellular compartmentalization. Cytomegalovirus infection results in disrupted white pulp compartmentalization of T and B cells in wild type mice (88). The low level of CCL21 expression in Lta−/− spleens (89) is reduced even further during infection with that virus, indicating that, in the adult, LT-independent pathways can contribute to maintenance of expression of lymphoid chemokines. Nevertheless, LT producing CD4+CD3 ltind cells are required to maintain T and B cell compartmentalization in the adult spleen (69). During infection with lymphocytic choriomeningitis virus, stromal cells and cellular organization are destroyed. Restoration is dependent on proliferation of CD4+CD3 cells and LTβR signaling (90), suggesting that the embryonic program can be reactivated under stress conditions.

TLOs are the most plastic and adaptable of the lymphoid tissues; lymphoid neogenesis can be induced by a variety of stimuli or inhibited by LTβR-Ig (summarized in (2)). Their nimbleness in this regard suggests that they might represent the most primitive tissues in the immune system. Tertiary lymphoid tissues can be ‘turned off’ (i.e., resolved) upon removal of the initial stimulus or after therapeutic intervention. For example, when β cells in the islets of Langerhans in Type I diabetes mellitus are destroyed, the loss of antigenic stimulus is accompanied by TLO resolution. Similarly LTβR-Ig treatment resolves established TLOs. These results recall those described above regarding the effects on established LNs of LTβR-Ig treatment (81, 84), again emphasizing the commonality of SLOs and TLOs.

Conclusions

In this communication, we have emphasized the similarities in structure and ontogeny of the various SLOs. Though a logical picture has emerged regarding the interaction of cytokines, chemokines and the cells that produce them, much remains to be determined. What is the nature and origin of ltini cells? How are they activated? What governs the precise anatomical location of SLOs? Do homeobox genes contribute to LNs and PPs? Do TLOs recapitulate ontogeny? The plasticity of SLOs and TLOs, the persistence of ltind and lto cells, and the ability of other cells to assume their functions, suggest that it may be possible to engineer lymphoid organs in individuals whose LNS are destroyed or non-functional due to surgical or genetic or acquired immunodeficiences.

Footnotes

1This work was supported by NIH R01 DK57731 and grants from the National Multiple Sclerosis Society RG 2394 and RG 4126-A-7

3Abbreviations used in this paper: SLO, secondary lymphoid organ; LN, lymph node; PP, Peyer’s patches; LT, lymphotoxin; PLN, peripheral lymph node; MLN, mucosal lymph node; MALT, mucosal associated lymphoid tissue; NALT, nasal associated lymphoid tissue; BALT, bronchus associated lymphoid tissue; ILF, isolated lymphoid follicle; TLO, tertiary lymphoid tissue; PNAd, peripheral node addressin; MAdCAM-1, mucosal associated adhesion molecule; HEV, high endothelial venule; DC, dendritic cell; FDC, follicular dendritic cell; RANK, receptor activator for NFκB; ltini, lymphoid tissue initiator; ltind, lymphoid tissue inducer; lto, lymphoid tissue organizer; LIGHT, lymphotoxin-related inducible ligand; MZ, marginal zone; FDC, follicular dendritic cell; HVEM, herpes virus entry mediator; NIK, NFκB kinase

DISCLOSURES

The authors have no financial conflict of interest

References

1. Steinman RM, Hawiger D, Liu K, Bonifaz L, Bonnyay D, Mahnke K, Iyoda T, Ravetch J, Dhodapkar M, Inaba K, Nussenzweig M. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann N Y Acad Sci. 2003;987:15–25. [PubMed]
2. Drayton DL, Liao S, Mounzer RH, Ruddle NH. Lymphoid organ development: from ontogeny to neogenesis. 2006;7:344–353. [PubMed]
3. Anderson AO, Anderson ND. Studies on the structure and permeability of the microvasculature in normal rat lymph nodes. Am J Pathol. 1975;80:387–418. [PubMed]
4. Gretz JE, Norbury CC, Anderson AO, Proudfoot AE, Shaw S. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J Exp Med. 2000;192:1425–1440. [PMC free article] [PubMed]
5. Mebius RE, Streeter PR, Michie S, Butcher EC, Weissman IL. A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+CD3− cells to colonize lymph nodes. Proc Natl Acad Sci. 1996;93:11019–11024. [PubMed]
6. Baekkevold ES, Yamanaka T, Palframan RT, Carlsen HS, Reinholt FP, von Andrian UH, Brandtzaeg P, Haraldsen G. The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J Exp Med. 2001;193:1105–1112. [PMC free article] [PubMed]
7. Cyster JG. Chemokines and cell migration in secondary lymphoid organs. Science. 1999;286:2098–2102. [PubMed]
8. Anderson AO, Shaw S. Conduit for privileged communications in the lymph node. Immunity. 2005;22:3–5. [PubMed]
9. Sixt M, Kanazawa N, Selg M, Samson T, Roos G, Reinhardt DP, Pabst R, Lutz MB, Sorokin L. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity. 2005;22:19–29. [PubMed]
10. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol. 2003;3:331–341. [PubMed]
11. Ying X, Chan K, Shenoy P, Hill M, Ruddle NH. Lymphotoxin plays a crucial role in the development and function of nasal-associated lymphoid tissue through regulation of chemokines and peripheral node addressin. Am J Pathol. 2005;166:135–146. [PubMed]
12. Xu B, Wagner N, Pham LN, Magno V, Shan Z, Butcher EC, Michie SA. Lymphocyte homing to bronchus-associated lymphoid tissue (BALT) is mediated by L-selectin/PNAd, alpha4beta1 integrin/VCAM-1, and LFA-1 adhesion pathways. J Exp Med. 2003;197:1255–1267. [PMC free article] [PubMed]
13. Taylor RT, Lugering A, Newell KA, Williams IR. Intestinal cryptopatch formation in mice requires lymphotoxin alpha and the lymphotoxin beta receptor. J Immunol. 2004;173:7183–7189. [PubMed]
14. Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function. J Immunol. 2003;170:5475–5482. [PubMed]
15. Lorenz RG, Newberry RD. Isolated lymphoid follicles can function as sites for induction of mucosal immune responses. Ann N Y Acad Sci. 2004;1029:44–57. [PubMed]
16. Akirav EA, Liao S, Ruddle NH. Lymphoid tissues and organs. In: Paul WE, editor. Fundamental Immunology. Wolters kluwer/Lippincott Williams and Wilkins; Philadelphia: 2008. pp. 27–55.
17. Mebius RE. Organogenesis of lymphoid tissues. Nat Rev Immunol. 2003;3:292–303. [PubMed]
18. Randall TD, Carragher DM, Rangel-Moreno J. Development of secondary lymphoid organs. Annu Rev Immunol. 2008;26:627–650. [PMC free article] [PubMed]
19. Granger GA, Williams TW. Lymphocyte cytotoxicity in vitro: activation and release of a cytotoxic factor. Nature. 1968;218:1253–1254. [PubMed]
20. Ruddle NH, Waksman BH. Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. 3. Analysis of mechanism. J Exp Med. 1968;128:1267–1279. [PMC free article] [PubMed]
21. Ruddle NH, Waksman BH. Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. II. Correlation of the in vitro response with skin reactivity. J Exp Med. 1968;128:1255–1265. [PMC free article] [PubMed]
22. Banks TA, Rouse BT, Kerley MK, Blair PJ, Godfrey VL, Kuklin NA, Bouley DM, Thomas J, Kanangat S, Mucenski ML. Lymphotoxin-alpha-deficient mice: effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol. 1995;155:1685–1693. [PubMed]
23. DeTogni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994;264:703–707. [PubMed]
24. Harmsen A, Kusser K, Hartson L, Tighe M, Sunshine MJ, Sedgwick JD, Choi Y, Littman DR, Randall TD. Cutting edge: organogenesis of nasal-associated lymphoid tissue (NALT) occurs independently of lymphotoxin-alpha (LT alpha) and retinoic acid receptor-related orphan receptor-gamma, but the organization of NALT is LT alpha dependent. J Immunol. 2002;168:986–990. [PubMed]
25. Alimzhanov MB, Kuprash DV, Kosco-Vilbois MH, Luz A, Turetskaya RL, Tarakhovsky A, Rajewsky K, Nedospasov SA, Pfeffer K. Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice. Proc Natl Acad Sci U S A. 1997;94:9302–9307. [PubMed]
26. Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity. 1997;6:491–500. [PubMed]
27. Soderberg KA, Linehan MM, Ruddle NH, Iwasaki A. MAdCAM-1 expressing sacral lymph node in the lymphotoxin beta-deficient mouse provides a site for immune generation following vaginal herpes simplex virus-2 infection. J Immunol. 2004;173:1908–1913. [PubMed]
28. Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K. The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity. 1998;9:59–70. [PubMed]
29. Scheu S, Alferink J, Potzel T, Barchet W, Kalinke U, Pfeffer K. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis. J Exp Med. 2002;195:1613–1624. [PMC free article] [PubMed]
30. Rennert PD, James D, Mackay F, Browning JL, Hochman PS. Lymph node genesis is induced by signaling through the lymphotoxin beta receptor. Immunity. 1998;9:71–79. [PubMed]
31. Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol. 2005;5:606–616. [PubMed]
32. Kuprash DV, Tumanov AV, Liepinsh DJ, Koroleva EP, Drutskaya MS, Kruglov AA, Shakhov AN, Southon E, Murphy WJ, Tessarollo L, Grivennikov SI, Nedospasov SA. Novel tumor necrosis factor-knockout mice that lack Peyer’s patches. Eur J Immunol. 2005;35:1592–1600. [PubMed]
33. Kuprash DV, Alimzhanov MB, Tumanov AV, Anderson AO, Pfeffer K, Nedospasov SA. TNF and lymphotoxin beta cooperate in the maintenance of secondary lymphoid tissue microarchitecture but not in the development of lymph nodes. J Immunol. 1999;163:6575–6580. [PubMed]
34. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, Armstrong A, Shen V, Bain S, Cosman D, Anderson D, Morrissey PJ, Peschon JJ, Schuh J. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13:2412–2424. [PubMed]
35. Kim D, Mebius RE, MacMicking JD, Jung S, Cupedo T, Castellanos Y, Rho J, Wong BR, Josien R, Kim N, Rennert PD, Choi Y. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med. 2000;192:1467–1478. [PMC free article] [PubMed]
36. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397:315–323. [PubMed]
37. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET, et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 1995;2:223–238. [PubMed]
38. Adachi S, Yoshida H, Honda K, Maki K, Saijo K, Ikuta K, Saito T, Nishikawa SI. Essential role of IL-7 receptor alpha in the formation of Peyer’s patch anlage. Int Immunol. 1998;10:1–6. [PubMed]
39. Luther SA, Ansel KM, Cyster JG. Overlapping roles of CXCL13, interleukin 7 receptor alpha, and CCR7 ligands in lymph node development. J Exp Med. 2003;197:1191–1198. [PMC free article] [PubMed]
40. Yoshida H, Naito A, Inoue J, Satoh M, Santee-Cooper SM, Ware CF, Togawa A, Nishikawa S. Different cytokines induce surface lymphotoxin-alphabeta on IL-7 receptor-alpha cells that differentially engender lymph nodes and Peyer’s patches. Immunity. 2002;17:823–833. [PubMed]
41. Park SY, Saijo K, Takahashi T, Osawa M, Arase H, Hirayama N, Miyake K, Nakauchi H, Shirasawa T, Saito T. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity. 1995;3:771–782. [PubMed]
42. Coles MC, Veiga-Fernandes H, Foster KE, Norton T, Pagakis SN, Seddon B, Kioussis D. Role of T and NK cells and IL7/IL7r interactions during neonatal maturation of lymph nodes. Proc Natl Acad Sci U S A. 2006;103:13457–13462. [PubMed]
43. Meier D, Bornmann C, Chappaz S, Schmutz S, Otten LA, Ceredig R, Acha-Orbea H, Finke D. Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity. 2007;26:643–654. [PubMed]
44. Ansel KM, V, Ngo N, Hyman PL, Luther SA, Forster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000;406:309–314. [PubMed]
45. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996;87:1037–1047. [PubMed]
46. Fukuyama S, Nagatake T, Kim DY, Takamura K, Park EJ, Kaisho T, Tanaka N, Kurono Y, Kiyono H. Cutting edge: Uniqueness of lymphoid chemokine requirement for the initiation and maturation of nasopharynx-associated lymphoid tissue organogenesis. J Immunol. 2006;177:4276–4280. [PubMed]
47. Yokota Y, Mansouri A, Mori S, Sugawara S, Adachi S, Nishikawa S, Gruss P. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature. 1999;397:702–706. [PubMed]
48. Eberl G, Littman DR. The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer’s patches. Immunol Rev. 2003;195:81–90. [PubMed]
49. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol. 2004;5:64–73. [PubMed]
50. Brendolan A, Rosado MM, Carsetti R, Selleri L, Dear TN. Development and function of the mammalian spleen. Bioessays. 2007;29:166–177. [PubMed]
51. Weih F, Caamano J. Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev. 2003;195:91–105. [PubMed]
52. Miyawaki S, Nakamura Y, Suzuka H, Koba M, Yasumizu R, Ikehara S, Shibata Y. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur J Immunol. 1994;24:429–434. [PubMed]
53. Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M, Kogishi K, Serikawa T, Honjo T. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet. 1999;22:74–77. [PubMed]
54. Drayton DL, Bonizzi G, Ying X, Liao S, Karin M, Ruddle NH. I kappa B kinase complex alpha kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue. J Immunol. 2004;173:6161–6168. [PubMed]
55. Oliver G. Lymphatic vasculature development. Nat Rev Immunol. 2004;4:35–45. [PubMed]
56. Johnson NC, Dillard ME, Baluk P, McDonald DM, Harvey NL, Frase SL, Oliver G. Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev. 2008;22:3282–3291. [PubMed]
57. Mishima K, Watabe T, Saito A, Yoshimatsu Y, Imaizumi N, Masui S, Hirashima M, Morisada T, Oike Y, Araie M, Niwa H, Kubo H, Suda T, Miyazono K. Prox1 induces lymphatic endothelial differentiation via Integrin {alpha}9 and other signaling cascades. Mol Biol Cell 2007 [PMC free article] [PubMed]
58. Eikelenboom P, Nassy JJ, Post J, Versteeg JC, Langevoort HL. The histogenesis of lymph nodes in rat and rabbit. Anat Rec. 1978;190:201–215. [PubMed]
59. Adachi S, Yoshida H, Kataoka H, Nishikawa S. Three distinctive steps in Peyer’s patch formation of murine embryo. Int Immunol. 1997;9:507–514. [PubMed]
60. Veiga-Fernandes H, Coles MC, Foster KE, Patel A, Williams A, Natarajan D, Barlow A, Pachnis V, Kioussis D. Tyrosine kinase receptor RET is a key regulator of Peyer’s patch organogenesis. Nature. 2007;446:547–551. [PubMed]
61. Mebius RE, Rennert P, Weissman IL. Developing lymph nodes collect CD4+CD3− LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity. 1997;7:493–504. [PubMed]
62. Yoshida H, Kawamoto H, Santee SM, Hashi H, Honda K, Nishikawa S, Ware CF, Katsura Y, Nishikawa SI. Expression of alpha(4)beta(7) integrin defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells. J Immunol. 2001;167:2511–2521. [PubMed]
63. White A, Carragher D, Parnell S, Msaki A, Perkins N, Lane P, Jenkinson E, Anderson G, Caamano JH. Lymphotoxin a-dependent and -independent signals regulate stromal organizer cell homeostasis during lymph node organogenesis. Blood. 2007;110:1950–1959. [PubMed]
64. Cupedo T, Vondenhoff MF, Heeregrave EJ, De Weerd AE, Jansen W, Jackson DG, Kraal G, Mebius RE. Presumptive lymph node organizers are differentially represented in developing mesenteric and peripheral nodes. J Immunol. 2004;173:2968–2975. [PubMed]
65. Okuda M, Togawa A, Wada H, Nishikawa S. Distinct activities of stromal cells involved in the organogenesis of lymph nodes and Peyer’s patches. J Immunol. 2007;179:804–811. [PubMed]
66. Lugering A, Kucharzik T, Soler D, Picarella D, Hudson JT, 3rd, Williams IR. Lymphoid precursors in intestinal cryptopatches express CCR6 and undergo dysregulated development in the absence of CCR6. J Immunol. 2003;171:2208–2215. [PubMed]
67. Katakai T, Suto H, Sugai M, Gonda H, Togawa A, Suematsu S, Ebisuno Y, Katagiri K, Kinashi T, Shimizu A. Organizer-like reticular stromal cell layer common to adult secondary lymphoid organs. J Immunol. 2008;181:6189–6200. [PubMed]
68. Taylor RT, Patel SR, Lin E, Butler BR, Lake JG, Newberry RD, Williams IR. Lymphotoxin-independent expression of TNF-related activation-induced cytokine by stromal cells in cryptopatches, isolated lymphoid follicles, and Peyer’s patches. J Immunol. 2007;178:5659–5667. [PubMed]
69. Kim MY, McConnell FM, Gaspal FM, White A, Glanville SH, Bekiaris V, Walker LS, Caamano J, Jenkinson E, Anderson G, Lane PJ. Function of CD4+CD3− cells in relation to B- and T-zone stroma in spleen. Blood. 2007;109:1602–1610. [PubMed]
70. Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville SH, McConnell FM, Scott HS, Penninger JM, Jenkinson EJ, Lane PJ, Anderson G. RANK signals from CD4(+)3(−) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med. 2007;204:1267–1272. [PMC free article] [PubMed]
71. Vondenhoff MF, Greuter M, Goverse G, Elewaut D, Dewint P, Ware CF, Hoorweg K, Kraal G, Mebius RE. LTbetaR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen. J Immunol. 2009;182:5439–5445. [PMC free article] [PubMed]
72. Fukuyama S, Hiroi T, Yokota Y, Rennert PD, Yanagita M, Kinoshita N, Terawaki S, Shikina T, Yamamoto M, Kurono Y, Kiyono H. Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR, and NIK signaling pathways but requires the Id2 gene and CD3(−)CD4(+)CD45(+) cells. Immunity. 2002;17:31–40. [PubMed]
73. Cuff CA, Schwartz J, Bergman CM, Russell KS, Bender JR, Ruddle NH. Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development. J Immunol. 1998;161:6853–6860. [PubMed]
74. Drayton DL, Ying X, Lee J, Lesslauer W, Ruddle NH. Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J Exp Med. 2003;197:1153–1163. [PMC free article] [PubMed]
75. McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity. 2008;28:445–453. [PubMed]
76. Ivanov, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–1133. [PubMed]
77. Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, Ivanov, Littman DR, O’Shea JJ. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med. 2009;206:35–41. [PMC free article] [PubMed]
78. Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, Fibbe WE, Cornelissen JJ, Spits H. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol. 2009;10:66–74. [PubMed]
79. Nakae S, Iwakura Y, Suto H, Galli SJ. Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. J Leukoc Biol. 2007;81:1258–1268. [PubMed]
80. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, Fujikado N, Tanahashi Y, Akitsu A, Kotaki H, Sudo K, Nakae S, Sasakawa C, Iwakura Y. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009;30:108–119. [PubMed]
81. Liao S, Ruddle NH. Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol. 2006;177:3369–3379. [PubMed]
82. Cupedo T, Jansen W, Kraal G, Mebius RE. Induction of secondary and tertiary lymphoid structures in the skin. Immunity. 2004;21:655–667. [PubMed]
83. Lane PJ, Gaspal FM, Kim MY. Two sides of a cellular coin: CD4(+)CD3− cells regulate memory responses and lymph-node organization. Nat Rev Immunol. 2005;5:655–660. [PMC free article] [PubMed]
84. Browning JL, Allaire N, Ngam-Ek A, Notidis E, Hunt J, Perrin S, Fava RA. Lymphotoxin-beta receptor signaling is required for the homeostatic control of HEV differentiation and function. Immunity. 2005;23:539–550. [PubMed]
85. Mackay F, Majeau GR, Hochman PS, Browning JL. Lymphotoxin beta receptor triggering induces activation of the nuclear factor kappaB transcription factor in some cell types. J Biol Chem. 1996;271:24934–24938. [PubMed]
86. Newberry RD, Lorenz RG. Organizing a mucosal defense. Immunol Rev. 2005;206:6–21. [PubMed]
87. Eberl G. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nat Rev Immunol. 2005;5:413–420. [PubMed]
88. Benedict CA, De Trez C, Schneider K, Ha S, Patterson G, Ware CF. Specific remodeling of splenic architecture by cytomegalovirus. PLoS Pathog. 2006;2:e16. [PMC free article] [PubMed]
89. Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, Browning JL, Sedgwick JD, Cyster JG. Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J Exp Med. 1999;189:403–412. [PMC free article] [PubMed]
90. Scandella E, Bolinger B, Lattmann E, Miller S, Favre S, Littman DR, Finke D, Luther SA, Junt T, Ludewig B. Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nat Immunol. 2008;9:667–675. [PubMed]