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1.  Constitutive Expression of the B7h Ligand for Inducible Costimulator on Naive B Cells Is Extinguished after Activation by Distinct B Cell Receptor and Interleukin 4 Receptor–mediated Pathways and Can Be Rescued by CD40 Signaling 
The recently described ligand–receptor pair, B7h–inducible costimulator (ICOS), is critical for germinal center formation and antibody responses. In contrast to the induced expression of the related costimulatory ligands B7.1 and B7.2, B7h is constitutively expressed on naive B cells and is surprisingly extinguished after antigen engagement and interleukin (IL)-4 cytokine signaling. Although signaling through both B cell receptor (BCR) and IL-4 receptor (R) converge on the extinction of B7h mRNA levels, BCR down-regulation occurs through Ca2+ mobilization, whereas IL-4R down-regulation occurs through a distinct Stat6-dependent pathway. During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R–mediated B7h down-regulation. These data suggest that the CD40–CD40 ligand signaling pathway regulates B7h expression on activated B cells and may control whether antigen-activated B cells can express B7h and costimulate cognate antigen–activated T cells through ICOS.
doi:10.1084/jem.20020298
PMCID: PMC2194020  PMID: 12093874
B7RP-1; ICOSL; GL-50; costimulation; CD40L
2.  IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells 
The Journal of Experimental Medicine  2010;207(13):2895-2906.
IL-27 signaling directly into T cells is needed for follicular T helper cell survival, germinal center formation, and the production of T cell–dependent high-affinity antibodies in mice.
Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (TFH) cells. TFH cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of TFH cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of TFH cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4+ T cells and the expression of TFH cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and TFH cell survival in a T cell–intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra−/− mice. Together, our data show a nonredundant role for IL-27 in the development of T cell–dependent antibody responses.
doi:10.1084/jem.20100064
PMCID: PMC3005229  PMID: 21098093
3.  Costimulatory molecule ICOS plays a critical role in the development of TH-17 and follicular T-helper cells by regulating c-Maf expression and IL-21 production 
Nature immunology  2008;10(2):167-175.
The inducible costimulatory molecule (ICOS) has been suggested to play an important role in the development of interleukin 17 (IL-17)-producing T helper cells (TH-17 cells) and of follicular helper cells (TFH cells), specialized helper T cells (CD4+CXCR5+ICOShigh) required for antibody class switching and germinal center formation. Here we show that ICOS, while not essential for the differentiation of TH-17 cells, was critical for maintaining effector-memory TH-17 cells as ICOS-deficient mice demonstrated a defect in the expansion of TH-17 cells after IL-23 stimulation. In addition, we found that TFH cells produced IL-17 and that ICOS-deficient mice demonstrated a reduced frequency of TFH with a defect in IL-17 production. Both TH-17 and TFH cells showed increased expression of the transcription factor c-Maf—normally associated with TH2 cells— and that loss of c-Maf results in a defect in IL-21 production, and consequently a defect in the maintenance of IL-23R expression and expansion of TH-17 and TFH cells. These data suggest that c-Maf induced by ICOS regulates IL-21 production that, in turn, regulates expansion of TH-17 cells and TFH cells.
doi:10.1038/ni.1690
PMCID: PMC2742982  PMID: 19098919
4.  A novel ICOS-independent, but CD28- and SAP-dependent, pathway of T cell-dependent, polysaccharide-specific humoral immunity in response to intact Streptococcus pneumoniae versus pneumococcal conjugate vaccine 
Polysaccharide (PS)- and protein-specific murine IgG responses to intact Streptococcus pneumoniae (Pn) are both dependent upon CD4+ T cell help, B7-dependent costimulation, and CD40/CD40-ligand interactions. However, the primary PS-, relative to protein-specific, IgG response terminates more rapidly, requires a shorter period of T cell help and B7-dependent costimulation, and fails to generate memory. In light of the critical role for ICOS/ICOS-ligand interactions in sustaining T cell-dependent Ig responses and promoting germinal center reactions, we hypothesized that this interaction was non-essential for PS-specific IgG responses to Pn. We now demonstrate that ICOS-/-, relative to WT, mice elicit a normal PS-specific IgG isotype response to Pn, despite marked inhibition of both the primary and secondary IgG anti-protein (i.e. PspA, PspC, and PsaA) response. A blocking anti-ICOS-ligand mAb injected during primary Pn immunization inhibits both the primary anti-protein response and the generation of protein-specific memory, but has no effect when injected during secondary immunization. In contrast to Pn, both PS- and protein-specific IgG responses to a pneumococcal conjugate vaccine are inhibited in ICOS-/- mice. ICOS-/- mice immunized with intact Pn or conjugate exhibit nearly complete abrogation in germinal center formation. Finally, although mice that lack the adaptor molecule SAP resemble ICOS-/- mice (and can exhibit decreased ICOS expression), we observe that the PS-, as well as protein-specific IgG responses to both Pn and conjugate are markedly defective in SAP-/- mice. These data define a novel T cell-, SAP-, and B7-dependent, but ICOS-independent, extrafollicular pathway of Ig induction.
PMCID: PMC2893027  PMID: 19050242
Rodent; Bacterial; Antibodies; Transgenic/Knockout mice; Vaccination
5.  ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity 
The Journal of Experimental Medicine  2008;205(12):2873-2886.
The role of specialized follicular helper T (TFH) cells in the germinal center has become well recognized, but it is less clear how effector T cells govern the extrafollicular response, the dominant pathway of high-affinity, isotype-switched autoantibody production in the MRL/MpJ-Faslpr (MRLlpr) mouse model of lupus. MRLlpr mice lacking the Icos gene have impaired extrafollicular differentiation of immunoglobulin (Ig) G+ plasma cells accompanied by defects in CXC chemokine receptor (CXCR) 4 expression, interleukin (IL) 21 secretion, and B cell helper function in CD4 T cells. These phenotypes reflect the selective loss of a population of T cells marked by down-regulation of P-selectin glycoprotein ligand 1 (PSGL-1; also known as CD162). PSGL-1lo T cells from MRLlpr mice express CXCR4, localize to extrafollicular sites, and uniquely mediate IgG production through IL-21 and CD40L. In other autoimmune strains, PSGL-1lo T cells are also abundant but may exhibit either a follicular or extrafollicular phenotype. Our findings define an anatomically distinct extrafollicular population of cells that regulates plasma cell differentiation in chronic autoimmunity, indicating that specialized humoral effector T cells akin to TFH cells can occur outside the follicle.
doi:10.1084/jem.20080840
PMCID: PMC2585848  PMID: 18981236
6.  The role of ICOS in the development of CD4 T cell help and the reactivation of memory T cells 
European Journal of Immunology  2007;37(7):1796-1808.
We have addressed the role of the inducible costimulator (ICOS) in the development of T cell help for B cells and in the generation, survival and reactivation of memory CD4 T cells and B cells. We find that while T cell help for all antibody isotypes (including IgG2c) is impaired in ICOS knockout (ICOS-KO) mice, the IFN-γ response is little affected, indicating a defect in helper function that is unrelated to cytokine production. In addition, the ICOS-negative T cells do not accumulate in B cell follicles. Secondary (memory), but not primary, clonal proliferation of antigen-specific B cells is impaired in ICOS-KO mice, as is the generation of secondary antibody-secreting cells. Analysis of endogenous CD4 memory cells in ICOS-KO mice, using MHC class II tetramers, reveals normal primary clonal expansion, formation of memory clones and long-term (10 wk) survival of memory cells, but defective expansion upon reactivation in vivo. The data point to a role of ICOS in supporting secondary, memory and effector T cell responses, possibly by influencing cell survival. The data also highlight differences in ICOS dependency of endogenous T cell proliferation in vivo compared to that of adoptively transferred TCR-transgenic T cells.
doi:10.1002/eji.200636661
PMCID: PMC2699381  PMID: 17549732
B cells; Cell differentiation; Costimulation; Memory; T cells
7.  CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo 
Cellular immunology  2009;259(2):177-184.
Previous work has shown ICOS can function independently of CD28, but whether either molecule can compensate for the other in vivo is not known. Since ICOS is a potent inducer of Th2 cytokines and linked to allergy and elevated serum IgE in humans, we hypothesized that augmenting ICOS costimulation in murine allergic airway disease may overcome CD28 deficiency. While ICOS was expressed on T cells from CD28−/− mice, Th2-mediated airway inflammation was not induced in CD28−/− mice by increased ICOS costimulation. Further, we determined if augmenting CD28 costimulation could compensate for ICOS deficiency. ICOS−/− mice had a defect in airway eosinophilia that was not overcome by augmenting CD28 costimulation. CD28 costimulation also did not fully compensate for ICOS for antibody responses, germinal center formation or the development of follicular B helper T cells. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.
doi:10.1016/j.cellimm.2009.06.013
PMCID: PMC2748173  PMID: 19646680
Costimulation; CD28; ICOS; follicular B helper T cells; Rodent; Th2 Cells; Antibodies; Allergy; Asthma
8.  ICOS Costimulation Expands Th2 Immunity by Augmenting Migration of Lymphocytes to Draining Lymph Nodes1 
The T cell costimulatory molecule ICOS regulates Th2 effector function in allergic airway disease. Recently, several studies with ICOS−/− mice have also demonstrated a role for ICOS in Th2 differentiation. To determine the effects of ICOS on the early immune response, we investigated augmenting ICOS costimulation in a Th2-mediated immune response to Schistosoma mansoni antigens. We found that augmenting ICOS costimulation with B7RP-1-Fc increased the accumulation of T and B cells in the draining lymph nodes post-immunization. Interestingly, the increased numbers were due in part to increased migration of undivided antigen-specific TCR transgenic T cells and surprisingly B cells, as well as non-TCR transgenic T cells. B7RP-1-Fc also increased the levels of the chemokines, CCL21 and CXCL13, in the draining lymph node, suggesting ICOS costimulation contributes to migration by direct or indirect effects on, dendritic cells, stromal cells and high endothelial venules. Further, the effects of B7RP-1-Fc were not dependent on immunization. Our data support a model in which ICOS costimulation augments the pool of lymphocytes in the draining lymph nodes leading to an increase in the frequency of potentially reactive T and B cells.
PMCID: PMC2560985  PMID: 18606653
Costimulation; Th1/Th2 cells; B cells; Rodent; Spleen and Lymph Nodes
9.  Regulation of T cell response by blocking the ICOS signal with the B7RP-1-specific small antibody fragment isolated from human antibody phage library 
mAbs  2009;1(5):453-461.
A costimulatory signal is required for the full activation of T cells, in addition to the antigen-specific signal via the T cell receptor. The inducible costimulator, ICOS is one of the costimulatory molecules that play an essential role in this process, particularly in the expansion or the development of effector T cells. As blocking of the interaction between ICOS and its ligand, B7RP-1, suppresses the T cell response, it can be applied to the treatment of allograft rejection or autoimmune diseases. Here, we isolated four scFv clones that were specific to human B7RP-1 by biopanning a human antibody phage library. We found that three of these clones inhibited the interaction between ICOS-Fc and B7RP-1-Fc. These inhibitory clones not only recognized B7RP-1 molecules expressed on B cells, as assessed by FACS, but also exhibited inhibitory activity in a proliferation assay of T cells stimulated with anti-CD3 mAb and B7RP-1-Fc. Finally, the suppression effect of the scFv on the allogenic immune response was examined using a mixed lymphocyte reaction assay, which demonstrated a successful inhibition of the allogenic reaction, in spite of the high dose needed for complete inhibition (360 nM).
PMCID: PMC2759495  PMID: 20065650
costimulatory signal; B7RP-1; ICOS; T-cell proliferation; antibody fragment; scFv; allogenic reaction
10.  Inducible Costimulator Expression Regulates the Magnitude of Th2-Mediated Airway Inflammation by Regulating the Number of Th2 Cells 
PLoS ONE  2009;4(11):e7525.
Background
Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5′ promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology.
Methodology/Principal Findings
We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS+/+ and ICOS+/− mice in a Th2 model of airway inflammation, we found that T cells from the ICOS+/− mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS+/− mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS+/− is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4.
Conclusion
These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation.
doi:10.1371/journal.pone.0007525
PMCID: PMC2768787  PMID: 19888475
11.  Role for Inducible Costimulator in Control of Salmonella enterica Serovar Typhimurium Infection in Mice  
Infection and Immunity  2006;74(2):1050-1061.
Inducible costimulator (ICOS) is expressed on activated T cells and plays a key role in sustaining and enhancing the effector function of CD4 T cells. Given the function of this molecule in sustaining T-cell responses, we reasoned that ICOS might play an important role in a prolonged infection model, such as Salmonella infection of mice. To test this hypothesis, wild-type (WT) and ICOS-deficient (ICOS−/−) mice were infected systemically with a Salmonella enterica serovar Typhimurium strain expressing the chicken ovalbumin gene (Salmonella-OVA). ICOS−/− mice exhibited greater splenomegaly than WT mice and showed delayed bacterial clearance. The acquired immune response in this model was slow to develop. Maximal T-cell responses to Salmonella-OVA were detected at 3 weeks postinfection in both WT and ICOS−/− mice. CD4 T-cell-dependent gamma interferon production and a class switch to immunoglobulin G2a were severely reduced in ICOS−/− mice. ICOS−/− mice also exhibited a substantial defect in antigen-specific CD8 T-cell responses. In vitro, the effect of anti-ICOS on CD8 T-cell division was greater when CD8 T cells rather than CD4 T cells expressed ICOS, suggesting that the in vivo effects of ICOS on CD8 T cells could be direct. Taken together, these studies show that ICOS plays a critical role in control of Salmonella infection in mice, with effects on antibody, Th1, and CD8 T-cell responses.
doi:10.1128/IAI.74.2.1050-1061.2006
PMCID: PMC1360312  PMID: 16428752
12.  Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand 
Although there is evidence for distinct roles of myeloid dendritic cells (DCs [mDCs]) and plasmacytoid pre-DCs (pDCs) in regulating T cell–mediated adaptive immunity, the concept of functional DC subsets has been questioned because of the lack of a molecular mechanism to explain these differences. In this study, we provide direct evidence that maturing mDCs and pDCs express different sets of molecules for T cell priming. Although both maturing mDCs and pDCs upregulate the expression of CD80 and CD86, only pDCs upregulate the expression of inducible costimulator ligand (ICOS-L) and maintain high expression levels upon differentiation into mature DCs. High ICOS-L expression endows maturing pDCs with the ability to induce the differentiation of naive CD4 T cells to produce interleukin-10 (IL-10) but not the T helper (Th)2 cytokines IL-4, -5, and -13. These IL-10–producing T cells are T regulatory cells, and their generation by ICOS-L is independent of pDC-driven Th1 and Th2 differentiation, although, in the later condition, some contribution from endogenous IL-4 cannot be completely ruled out. Thus, in contrast to mDCs, pDCs are poised to express ICOS-L upon maturation, which leads to the generation of IL-10–producing T regulatory cells. Our findings demonstrate that mDC and pDCs are intrinsically different in the expression of costimulatory molecules that drive distinct types of T cell responses.
doi:10.1084/jem.20061660
PMCID: PMC2118437  PMID: 17200410
13.  Inducible costimulator is essential for collagen-induced arthritis 
Journal of Clinical Investigation  2003;111(5):701-706.
CD4+ helper Th cells play a major role in the pathogenesis of rheumatoid arthritis. Th cell activation, differentiation, and immune function are regulated by costimulatory molecules. Inducible costimulator (ICOS) is a novel costimulatory receptor expressed on activated T cells. We, as well as others, recently demonstrated its importance in Th2 cytokine expression and Ab class switching by B cells. In this study, we examined the role of ICOS in rheumatoid arthritis using a collagen-induced arthritis model. We found that ICOS knockout mice on the DBA/1 background were completely resistant to collagen-induced arthritis and exhibited absence of joint tissue inflammation. These mice, when immunized with collagen, exhibited reduced anti-collagen IgM Ab’s in the initial stage and IgG2a Ab’s at the effector phase of collagen-induced arthritis. Furthermore, ICOS regulates the in vitro and in vivo expression of IL-17, a proinflammatory cytokine implicated in rheumatoid arthritis. These data indicate that ICOS is essential for collagen-induced arthritis and may suggest novel means for treating patients with rheumatoid arthritis.
doi:10.1172/JCI200317321
PMCID: PMC151904  PMID: 12618524
14.  ICOS, CD40, and Lymphotoxin β Receptors Signal Sequentially and Interdependently to Initiate a Germinal Center Reaction1 
Germinal center (GC) responses to T-dependent Ags require effective collaboration between Th cells, activated B cells, and follicular dendritic cells within a highly organized microenvironment. Studies using gene-targeted mice have highlighted nonredundant molecules that are key for initiating and maintaining the GC niche, including the molecules of the ICOS, CD40, and lymphotoxin (LT) pathways. Signaling through ICOS has multiple consequences, including cytokine production, expression of CD40L on Th cells, and differentiation into CXCR5+ follicular Th cells, all of which are important in the GC reaction. We have therefore taken advantage of ICOS−/− mice to dissect which downstream elements are required to initiate the formation of GC. In the context of a T-dependent immune response, we found that GC B cells from ICOS−/− mice express lower levels of LTαβ compared with wild-type GC B cells in vivo, and stimulation of ICOS on T cells induces LTαβ on B cells in vitro. Administration of agonistic anti-LTβ receptor Ab was unable to restore the GC response in ICOS−/− mice, suggesting that additional input from another pathway is required for optimal GC generation. In contrast, treatment with agonistic anti-CD40 Ab in vivo recovered GC networks and restored LTαβ expression on GC B cells in ICOS−/− mice, and this effect was dependent on LTβ receptor signaling. Collectively, these data demonstrate that ICOS activation is a prerequisite for the up-regulation of LTαβ on GC B cells in vivo and provide a model for cooperation between ICOS, CD40, and LT pathways in the context of the GC response.
PMCID: PMC2735203  PMID: 18250437
15.  T Cells That Promote B-Cell Maturation in Systemic Autoimmunity 
Immunological Reviews  2012;247(1):160-171.
Summary
Follicular helper T (Tfh) cells play an essential role in helping B cells generate antibodies upon pathogen encounters. Such T-cell help classically occurs in germinal centers (GCs) located in B-cell follicles of secondary lymphoid organs, a site of immunoglobulin affinity maturation and isotype switching. B-cell maturation also occurs extrafollicularly, in the red pulp of the spleen and medullary cords in lymph nodes, with plasma cell formation and antibody production. Development of extrafollicular foci (EF) in T-cell-dependent (TD) immune responses is reliant upon CD4+ T cells with characteristics of Tfh cells. Pathogenic autoantibodies, arising from self-reactive B cells having undergone somatic hypermutation with affinity selection and class switching within GCs and EF, are major contributors to the end-organ injury in systemic autoimmunity. B cells maturing to produce autoantibodies in systemic autoimmune diseases, like those in normal immune responses, largely require T-helper cells. This review highlights Tfh cell development as an introduction to a more in-depth discussion of human Tfh cells and blood borne cells with similar features and the role of these cells in promotion of systemic autoimmunity.
doi:10.1111/j.1600-065X.2012.01122.x
PMCID: PMC3334351  PMID: 22500839
extrafollicular foci; follicular helper T cells; germinal centers; human; lupus
16.  Plasmacytoid Dendritic Cells Promote Immunosuppression in Ovarian Cancer via ICOS Costimulation of Foxp3+ T-Regulatory Cells 
Cancer research  2012;72(20):5240-5249.
Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Despite its immunogenicity, effective antitumor responses are limited, due, in part, to the presence of forkhead box protein 3–positive (Foxp3+) T regulatory (Treg) cells in the tumor microenvironment. However, the mechanisms that regulate the accumulation and the suppressive function of these Foxp3+ Treg cells are poorly understood. Here, we found that the majority of Foxp3+ Treg cells accumulating in the tumor microenvironment of EOCs belong to the subset of Foxp3+ Treg cells expressing inducible costimulator (ICOS). The expansion and the suppressive function of these cells were strictly dependent on ICOS-L costimulation provided by tumor plasmacytoid dendritic cells (pDC). Accordingly, ICOS+Foxp3+Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS+ Foxp3+Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS+Treg cell subset being a stronger predictor than total Foxp3+Treg cells. These findings suggest an essential role for pDCs and ICOS-L in immunosuppression mediated by ICOS+ Foxp3+ Treg cells, leading to tumor progression in ovarian cancer.
doi:10.1158/0008-5472.CAN-12-2271
PMCID: PMC3652570  PMID: 22850422
17.  Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production 
The Journal of Experimental Medicine  2000;192(11):1545-1552.
Chemokines and their receptors have been identified as major regulators controlling the functional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD4+CXCR5+ cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4+CD45RO+CXCR5− cells, CD4+CD45RO+CXCR5+ tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4+CD45RO+CXCR5− population, suggesting that CXCR5+CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells “follicular B helper T cells” (TFH).
PMCID: PMC2193094  PMID: 11104797
CXC chemokine receptor 5; CC chemokine receptor 7; T cell homing; germinal centers; T helper cells
18.  FOLLICULAR HELPER T CELLS AS COGNATE REGULATORS OF B CELL IMMUNITY 
Current opinion in immunology  2009;21(3):266-273.
SUMMARY
Follicular helper T (TFH) cells are a class of helper T cells specialized in the cognate control of antigen-specific B cell immunity. Upon first contact with antigen-primed B cells, pre-germinal center effector TFH cells promote B cell clonal expansion, antibody isotype switch, plasma cell differentiation and the induction of germinal centers. In contrast, within germinal centers, TFH cells regulate the fate of antigen-specific GC B cells expressing high-affinity variant B cell receptors to promote memory B cell and long-lived plasma cell development. Recent studies unravel multiple signals controlling TFH development and functional sub-types of antigen-specific TFH cells, including memory TFH cells that accelerate memory B cell responses to antigen re-challenge in vivo.
doi:10.1016/j.coi.2009.05.010
PMCID: PMC2731669  PMID: 19502021
19.  Inducible Costimulator Protein (Icos) Controls T Helper Cell Subset Polarization after Virus and Parasite Infection 
It has been shown that certain pathogens can trigger efficient T cell responses in the absence of CD28, a key costimulatory receptor expressed on resting T cells. Inducible costimulator protein (ICOS) is an inducible costimulator structurally and functionally related to CD28. Here, we show that in the absence of CD28 both T helper cell type 1 (Th1) and Th2 responses were impaired but not abrogated after infection with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), and the nematode Nippostrongylus brasiliensis. Inhibition of ICOS in CD28-deficient mice further reduced Th1/Th2 polarization. Blocking of ICOS alone had a limited but significant capacity to downregulate Th subset development. In contrast, cytotoxic T lymphocyte (CTL) responses, which are regulated to a minor and major extent by CD28 after LCMV and VSV infection, respectively, remained unaffected by blocking ICOS. Together, our results demonstrate that ICOS regulates both CD28-dependent and CD28-independent CD4+ subset (Th1 and Th2) responses but not CTL responses in vivo.
PMCID: PMC1887704  PMID: 10880526
ICOS; CD28; Th1/Th2; Nippostrongylus brasiliensis; LCMV
20.  Emerging mechanisms of immune regulation: the extended B7 family and regulatory T cells 
Arthritis Research & Therapy  2004;6(5):208-214.
Whereas B7-1/B7-2 and CD28/cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) serve as the main switches regulating the clonal composition of activated naive T cells, other B7 family members fine-tune the expansion and properties of activated T cells. Inducible costimulatory molecule (ICOS)-B7h promotes T-dependent antibody isotype switching and expansion of effector cells. Effector T cells trafficking into inflamed tissues interact with antigen-presenting cells there and are regulated by PD-1 and its ligands. B7-H3 and B7x could control the interaction between effector T cells and the peripheral tissues. The different varieties of regulatory T cells could regulate both naive T cell activation and effector function through costimulatory receptor/ligands.
doi:10.1186/ar1225
PMCID: PMC546290  PMID: 15380035
antitumor immunity; autoimmunity; costimulation; inflammation; regulatory T cells
21.  Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection 
Journal of Virology  2012;86(13):7146-7157.
Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (TFH) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of TFH subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (TGC) as lymph node-resident CD4+ ICOS+ CXCR4+ CXCR5+ PSGL-1lo PD-1hi cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only TFH subsets missing in influenza virus-infected, germinal center-deficient SAP−/− mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as “extrafollicular” helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS+ subsets induced similar antibody levels in vitro, CXCR5-single-positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of TFH function.
doi:10.1128/JVI.06904-11
PMCID: PMC3416343  PMID: 22532671
22.  Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function 
The Journal of Experimental Medicine  2002;195(8):1033-1041.
Interaction between inducible costimulator (ICOS) and its ligand is implicated in the induction of cell-mediated and humoral immune responses. However, the molecular details of this interaction are unknown. We report here a mutagenesis analysis of residues in ICOS that are critical for ligand binding. A three-dimensional model of the extracellular immunoglobulin-like domain of ICOS was used to map the residues conserved within the CD28 family. This analysis identified a surface patch containing the characteristic “PPP” sequence and is conserved in human and mouse ICOS. Mutations in this region of human ICOS reduce or abolish ligand binding. Our results suggest that the ligand binding site in ICOS maps to a region overlapping yet distinct from the CD80/CD86 binding sites in CD28 and cytotoxic T lymphocyte antigen (CTLA)-4. Thus, the analysis suggests that differences in ligand binding specificity between these related costimulatory molecules have evolved by utilization of overlapping regions with different patterns of conserved and nonconserved residues. Two site-specific mutants generated in the course of our studies bound ICOS ligand with higher avidity than wild-type ICOS. An S76E mutant protein of ICOS blocked T cell costimulatory function of ICOS ligand and inhibited T cell response to allogeneic antigens superior to wild-type ICOS. Our studies thus identified critical residues involving in ICOS receptor–ligand interaction and provide new modulators for immune responses.
doi:10.1084/jem.20011607
PMCID: PMC2193694  PMID: 11956294
ICOS; CD28; molecular model; mutagenesis; avidity
23.  Inhibitors of mitogen-activated protein kinases differentially regulate costimulated T cell cytokine production and mouse airway eosinophilia 
Respiratory Research  2005;6(1):36.
Background
T cells play a dominant role in the pathogenesis of asthma. Costimulation of T cells is necessary to fully activate them. An inducible costimulator (ICOS) of T cells is predominantly expressed on Th2 cells. Therefore, interference of signaling pathways precipitated by ICOS may present new therapeutic options for Th2 dominated diseases such as asthma. However, these signaling pathways are poorly characterized in vitro and in vivo.
Methods
Human primary CD4+ T cells from blood were activated by beads with defined combinations of surface receptor stimulating antibodies and costimulatory receptor ligands. Real-time RT-PCR was used for measuring the production of cytokines from activated T cells. Activation of mitogen activated protein kinase (MAPK) signaling pathways leading to cytokine synthesis were investigated by western blot analysis and by specific inhibitors. The effect of inhibitors in vivo was tested in a murine asthma model of late phase eosinophilia. Lung inflammation was assessed by differential cell count of the bronchoalveolar lavage, determination of serum IgE and lung histology.
Results
We showed in vitro that ICOS and CD28 are stimulatory members of an expanding family of co-receptors, whereas PD1 ligands failed to co-stimulate T cells. ICOS and CD28 activated different MAPK signaling cascades necessary for cytokine activation. By means of specific inhibitors we showed that p38 and ERK act downstream of CD28 and that ERK and JNK act downstream of ICOS leading to the induction of various T cell derived cytokines. Using a murine asthma model of late phase eosinophilia, we demonstrated that the ERK inhibitor U0126 and the JNK inhibitor SP600125 inhibited lung inflammation in vivo. This inhibition correlated with the inhibition of Th2 cytokines in the BAL fluid. Despite acting on different signaling cascades, we could not detect synergistic action of any combination of MAPK inhibitors. In contrast, we found that the p38 inhibitor SB203580 antagonizes the action of the ERK inhibitor U0126 in vitro and in vivo.
Conclusion
These results demonstrate that the MAPKs ERK and JNK may be suitable targets for anti-inflammatory therapy of asthma, whereas inhibition of p38 seems to be an unlikely target.
doi:10.1186/1465-9921-6-36
PMCID: PMC1131927  PMID: 15833106
24.  Increased IL-12 inhibits B cells' differentiation to germinal center cells and promotes differentiation to short-lived plasmablasts 
The Journal of Experimental Medicine  2008;205(10):2437-2448.
B cells activated by antigen in T cell–dependent immune responses can become short-lived plasma cells, which remain in the spleen, or germinal center–derived memory or plasma cells, which show evidence of affinity maturation and, in the case of plasma cells, migrate to the bone marrow. We show that this cell fate decision can be governed by the cytokine environment engendered by activated dendritic cells (DCs). DCs from mice lacking the Fc receptor γ chain exhibited an activated phenotype in vitro. They secreted more of the proinflammatory cytokine IL-12, which led to the preferential generation of short-lived splenic plasma cells, with ensuing low affinity antibodies and a diminished recall response. Understanding the factors that regulate antigen-activated B cell differentiation and memory cell formation has implications for both antibody-mediated autoimmune disease and protective antibody responses.
doi:10.1084/jem.20070731
PMCID: PMC2556778  PMID: 18809711
25.  Enhanced Inducible Costimulator Ligand (ICOS-L) Expression on Dendritic Cells in Interleukin-10 Deficiency and Its Impact on T-Cell Subsets in Respiratory Tract Infection 
Molecular Medicine  2013;19(1):346-356.
An association between inducible costimulator ligand (ICOS-L) expression and interleukin (IL)-10 production by dendritic cells (DCs) has been commonly found in infectious disease. DCs with higher ICOS-L expression and IL-10 production are reportedly more efficient in inducing regulatory T cells (Tregs). Here we use the Chlamydia muridarum (Cm) lung infection model in IL-10 knockout (KO) mice to test the relationship between IL-10 production and ICOS-L expression by DCs. We examined ICOS-L expression, the development of T-cell subsets, including Treg, Th17 and Th1 cell, in the background of IL-10 deficiency and its relationship with ICOS-L/ICOS signaling after infection. Surprisingly, we found that the IL-10 KO mice exhibited significantly higher ICOS-L expression by DCs. Moreover, IL-10 KO mice showed lower Tregs but higher Th17 and Th1 responses, but only the Th17 response depended on ICOS signaling. Consistently, most of the Th17 cells were ICOS+, whereas most of the Th1 cells were ICOS− in the infected mice. Furthermore, neutralization of IL-17 in IL-10 KO mice significantly exacerbated lung infection. The data suggest that ICOS-L expression on DC may be negatively regulated by IL-10 and that ICOS-L expression on DC in the presence or absence of IL-10 costimulation may promote Treg or Th17 response, without significant impact on Th1.
doi:10.2119/molmed.2013.00035
PMCID: PMC3883961  PMID: 24100657

Results 1-25 (929099)