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1.  Molecular programming of B cell memory 
Nature reviews. Immunology  2011;12(1):24-34.
The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information — resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes — has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming.
doi:10.1038/nri3128
PMCID: PMC3947622  PMID: 22158414
2.  STAT5 is a potent negative regulator of TFH cell differentiation 
Interleukin 2, STAT5, and Blimp-1 work together to suppress differentiation of follicular helper T cells in mice.
Follicular helper T cells (TFH cells) constitute the CD4+ T cell subset that is specialized to provide help to germinal center (GC) B cells and, consequently, mediate the development of long-lived humoral immunity. TFH cell differentiation is driven by the transcription factor Bcl6, and recent studies have identified cytokine and cell–cell signals that drive Bcl6 expression. However, although TFH dysregulation is associated with several major autoimmune diseases, the mechanisms underlying the negative regulation of TFH cell differentiation are poorly understood. In this study, we show that STAT5 inhibits TFH cell differentiation and function. Constitutive STAT5 signaling in activated CD4+ T cells selectively blocked TFH cell differentiation and GCs, and IL-2 signaling was a primary inducer of this pathway. Conversely, STAT5-deficient CD4+ T cells (mature STAT5fl/fl CD4+ T cells transduced with a Cre-expressing vector) rapidly up-regulated Bcl6 expression and preferentially differentiated into TFH cells during T cell priming in vivo. STAT5 signaling failed to inhibit TFH cell differentiation in the absence of the transcription factor Blimp-1, a direct repressor of Bcl6 expression and TFH cell differentiation. These results demonstrate that IL-2, STAT5, and Blimp-1 collaborate to negatively regulate TFH cell differentiation.
doi:10.1084/jem.20111174
PMCID: PMC3281266  PMID: 22271576
3.  Loss of Circulating CD4 T Cells with B Cell Helper Function during Chronic HIV Infection 
PLoS Pathogens  2014;10(1):e1003853.
The interaction between follicular T helper cells (TFH) and B cells in the lymph nodes and spleen has a major impact on the development of antigen-specific B cell responses during infection or vaccination. Recent studies described a functional equivalent of these cells among circulating CD4 T cells, referred to as peripheral TFH cells. Here, we characterize the phenotype and in vitro B cell helper activity of peripheral TFH populations, as well as the effect of HIV infection on these populations. In co-culture experiments we confirmed CXCR5+ cells from HIV-uninfected donors provide help to B cells and more specifically, we identified a CCR7highCXCR5highCCR6highPD-1high CD4 T cell population that secretes IL-21 and enhances isotype-switched immunoglobulin production. This population is significantly decreased in treatment-naïve, HIV-infected individuals and can be recovered after anti-retroviral therapy. We found impaired immunoglobulin production in co-cultures from HIV-infected individuals and found no correlation between the frequency of peripheral TFH cells and memory B cells, or with neutralization activity in untreated HIV infection in our cohort. Furthermore, we found that within the peripheral TFH population, the expression level of TFH-associated genes more closely resembles a memory, non-TFH population, as opposed to a TFH population. Overall, our data identify a heterogeneous population of circulating CD4 T cells that provides in vitro help to B cells, and challenges the origin of these cells as memory TFH cells.
Author Summary
Follicular T helper cells (TFH) interact with B cells within germinal centers of lymphoid tissue to promote the survival, isotype switching and generation of high affinity memory B cells and plasma cells. Recently, a population of circulating CD4 T cells that shares phenotypic and functional characteristics with TFH cells, named peripheral TFH cells, has been identified. The relationship between peripheral TFH cells in the blood and TFH cells within the lymphoid tissue remains unclear, and whether or not peripheral TFH cells can provide insight into T cell and B cell dynamics within lymphoid tissue during infection or vaccination is not understood. Here we characterize peripheral TFH cells and show that unlike TFH cells, peripheral TFH cells secrete a diverse array of cytokines and decrease, rather than increase, during chronic HIV infection. Furthermore, we did not observe a relationship between peripheral TFH cells and memory B cells, or with the production of neutralizing antibodies to HIV. Overall, our data indicate that while peripheral TFH cells share some characteristics with TFH cells, they may not represent a good surrogate to study T cell and B cell dynamics within lymphoid tissue.
doi:10.1371/journal.ppat.1003853
PMCID: PMC3911819  PMID: 24497824
4.  Germinal Center T Follicular Helper Cell IL-4 Production Is Dependent on Signaling Lymphocytic Activation Molecule Receptor (CD150) 
CD4 T cell help is critical for the generation and maintenance of germinal centers (GCs), and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP [SH2D1A]) expression in CD4 T cells is essential for GC development. However, SAP-deficient mice have only a moderate defect in TFH differentiation, as defined by common TFH surface markers. CXCR5+ TFH cells are found within the GC, as well as along the boundary regions of T/B cell zones. In this study, we show that GC-associated T follicular helper (GC TFH) cells can be identified by their coexpression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. GC TFH cells are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH cell subset and SAP− TFH cells are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that uses SAP signaling, is specifically required for IL-4 production by GC TFH cells. GC TFH cells require IL-4 and -21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by GC CD4 T cells but not in TFH cell and GC TFH cell differentiation.
doi:10.4049/jimmunol.0903505
PMCID: PMC2913439  PMID: 20525889
5.  The origins, function, and regulation of T follicular helper cells 
The Journal of Experimental Medicine  2012;209(7):1241-1253.
The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4+ T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell–dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.
doi:10.1084/jem.20120994
PMCID: PMC3405510  PMID: 22753927
6.  Bcl6 Mediates the Development of T Follicular Helper Cells 
Science (New York, N.Y.)  2009;325(5943):1001-1005.
A fundamental function of CD4+ helper T (TH) cells is the regulation of B cell–mediated humoral immunity. Development of T follicular helper (TFH) cells that provide help to B cells is mediated by the cytokines interleukin-6 and interleukin-21 but is independent of TH1, TH2, and TH17 effector cell lineages. Here, we characterize the function of Bcl6, a transcription factor selectively expressed in TFH cells. Bcl6 expression is regulated by interleukin-6 and interleukin-21. Bcl6 overexpression induced TFH-related gene expression and inhibited other TH lineage cell differentiation in a DNA binding–dependent manner. Moreover, Bcl6 deficiency in T cells resulted in impaired TFH cell development and germinal center reactions, and altered production of other effector T cell subsets. Our data thus illustrate that Bcl6 is required for programming of TFH cell generation.
doi:10.1126/science.1176676
PMCID: PMC2857334  PMID: 19628815
7.  Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation 
Science (New York, N.Y.)  2009;325(5943):1006-1010.
Effective B cell–mediated immunity and antibody responses often require help from CD4+ T cells. It is thought that a distinct CD4+ effector T cell subset, called T follicular helper cells (TFH), provides this help; however, the molecular requirements for TFH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits TFH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that TFH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiation.
doi:10.1126/science.1175870
PMCID: PMC2766560  PMID: 19608860
8.  Functional and Epigenetic Analyses of In Vitro-generated and In Vivo-derived Interleukin-21-Producing Follicular T helper-like cells 
Immunity  2011;35(4):622-632.
Summary
Follicular T helper cells (Tfh) provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated Protein (SAP) prevent GC formation due to defective T-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally-competent “Tfh-like” cells that expressed Interleukin-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2 and Th17 cells could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in non-Tfh cells, supporting the concept of plasticity between Tfh and other Th cell populations.
doi:10.1016/j.immuni.2011.07.015
PMCID: PMC3235706  PMID: 22018472
9.  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
10.  Transcriptional regulation of follicular T-helper (Tfh) cells 
Immunological reviews  2013;252(1):139-145.
Summary
T-follicular helper (Tfh) cells are a new subset of effector CD4+ T cells that are specialized in helping B cells in the germinal center reaction. Tfh cells are distinct from other established CD4+ T-cell lineages, Th1, Th2, Th17, and T-regulatory cells, in their gene expression profiles. Tfh cell differentiation results from a network of transcriptional regulation by a master transcriptional factor Bcl6 as well as IRF4, c-Maf, Batf, and STAT3/5. During Tfh cell ontogeny, increased CXCR5 expression directs activated T-cell migration to the follicles, and their interaction with B cells leads to Bcl6 upregulation, which helps establish effector and memory Tfh cell program. This review summarizes the recent progress in molecular mechanisms underlying Tfh differentiation and discusses the future perspectives for this important area of research.
doi:10.1111/imr.12040
PMCID: PMC3579502  PMID: 23405901
11.  Regulatory T Cell-Mediated Control of Autoantibody-Induced Inflammation 
Autoimmune inflammation including autoantibody-induced inflammation is responsible for the lethal organ damage. Autoantibody-induced inflammation can be separated in two components, autoantibody production, and local inflammatory responses. Accumulating evidence has suggested that regulatory T cells (Treg) control both antibody production and the numbers and functions of effector cells such as innate cells and T helper cells. Autoantibodies are produced by both the follicular and extrafollicular pathways. Recently, follicular regulatory T cells (TFR) and Qa-1 restricted CD8+ Treg were identified as populations that are capable of suppressing follicular T helper cell (TFH)-mediated antibody production. In local inflammation, CD4+CD25+Foxp3+ Treg have the capacity to control inflammation by suppressing cytokine production in T helper cells. Although complement proteins contribute to autoantibody-induced local inflammation by activating innate cells, Treg including CD4+CD25+Foxp3+ Treg are able to suppress innate cells, chiefly via IL-10 production. IL-10-secreting T cells such as T regulatory type I (Tr1) and Tr1-like cells might also play roles in the control of Th17 and innate cells. Therefore, several kinds of Tregs have the potential to control autoimmune inflammation by suppressing both autoantibody production and the local inflammatory responses induced by autoantibodies.
doi:10.3389/fimmu.2012.00028
PMCID: PMC3342324  PMID: 22566912
chronic inflammation; autoantibody; regulatory T cells; IL-10; Tr1 cells
12.  T Follicular Helper Cell Dynamics in Germinal Centers 
Science (New York, N.Y.)  2013;341(6146):673-677.
T follicular helper cells (TFH) are a specialized subset of effector T cells that provide help to and thereby select high-affinity B cells in germinal centers (GCs). To examine the dynamic behavior of TFH cells in GCs in mice we combined two-photon microscopy and optical highlighting using a photoactivatable fluorescent reporter. Unlike GC B cells, which are clonally restricted, TFH distributed among all GCs in lymph nodes and continually emigrated into the follicle and neighboring GCs. Moreover, newly activated TFH cells invaded pre-existing GCs, where they contributed to B cell selection and plasmablast differentiation. Our data suggest that dynamic exchange of TFH between GCs ensures maximal diversification of T cell help and their ability to enter ongoing GCs accommodates antigenic variation during the immune response.
doi:10.1126/science.1241680
PMCID: PMC3941467  PMID: 23887872
13.  Subspecialization of Cxcr5+ T Cells 
The Journal of Experimental Medicine  2001;193(12):1373-1382.
The T helper (Th) cell pool is composed of specialized cells with heterogeneous effector functions. Apart from Th1 and 2 cells, CXCR5+ T cells have been suggested to be another type of effector T cell specialized for B cell help. We show here that CXCR5+ T cells are heterogeneous, and we identify subsets of CXCR5+ CD4 T cells that differ in function and microenvironmental localization in secondary lymphoid tissues. CD57+CXCR5 T cells, hereafter termed germinal center Th (GC-Th) cells, are localized only in GCs, lack CCR7, and are highly responsive to the follicular chemokine B lymphocyte chemoattractant but not to the T cell zone EBI1-ligand chemokine. Importantly, GC-Th cells are much more efficient than CD57−CXCR5+ T cells or CXCR5− T cells in inducing antibody production from B cells. Consistent with their function, GC-Th cells produce elevated levels of interleukin 10 upon stimulation which, with other cytokines and costimulatory molecules, may help confer their B cell helper activity. Our results demonstrate that CXCR5+ T cells are functionally heterogeneous and that the GC-Th cells, a small subset of CXCR5+ T cells, are the key helpers for B cell differentiation and antibody production in lymphoid tissues.
PMCID: PMC2193300  PMID: 11413192
germinal center; chemokine receptor; CXCR5; B cell help; T helper cells
14.  Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation 
PLoS ONE  2011;6(8):e22848.
IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17) share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID), defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21lowCD38low). Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.
doi:10.1371/journal.pone.0022848
PMCID: PMC3149619  PMID: 21826211
15.  Phenotype, effector function, and tissue localization of PD-1-expressing human follicular helper T cell subsets 
BMC Immunology  2011;12:53.
Background
It is well established that PD-1 is expressed by follicular T cells but its function in regulation of human T helper cells has been unclear. We investigated the expression modality and function of PD-1 expressed by human T cells specialized in helping B cells.
Results
We found that PD-1-expressing T cells are heterogeneous in PD-1 expression. We identified three different PD-1-expressing memory T cell subsets (i.e. PD-1low (+), PD-1medium (++), and PD-1high (+++) cells). PD-1+++ T cells expressed CXCR5 and CXCR4 and were localized in the rim of germinal centers. PD-1+ or PD-1++ cells expressed CCR7 and were present mainly in the T cell area or other parts of the B cell follicles. Utilizing a novel antigen density-dependent magnetic sorting (ADD-MS) method, we isolated the three T cell subsets for functional characterization. The germinal center-located PD-1+++ T cells were most efficient in helping B cells and in producing IL-21 and CXCL13. Other PD-1-expressing T cells, enriched with Th1 and Th17 cells, were less efficient than PD-1+++ T cells in these capacities. PD-1+++ T cells highly expressed Ki-67 and therefore appear active in cell activation and proliferation in vivo. IL-2 is a cytokine important for proliferation and survival of the PD-1+++ T cells. In contrast, IL-21, while a major effector cytokine produced by the PD-1-expressing T helper cells, had no function in generation, survival, or proliferation of the PD-1-expressing helper T cells at least in vitro. PD-1 triggering has a suppressive effect on the proliferation and B cell-helping function of PD-1+++ germinal center T cells.
Conclusion
Our results revealed the phenotype and effector function of PD-1-expressing T helper cell subsets and indicate that PD-1 restrains the B cell-helping function of germinal center-localized T cells to prevent excessive antibody response.
doi:10.1186/1471-2172-12-53
PMCID: PMC3184275  PMID: 21914188
16.  FOLLICULAR HELPER T CELLS: LINEAGE AND LOCATION 
Immunity  2009;30(3):324-335.
Follicular helper T (TFH) cells are the class of effector TH cells that regulates the stepwise development of antigen-specific B cell immunity in vivo. Deployment of CXCR5+ TFH cells to B cell zones of lymphoid tissues and stable cognate interactions with B cells are central to the delivery of antigen-specific TFH function. Recent advances help to unravel distinctive elements of developmental programming for TFH cells and unique effector TFH functions focused on antigen-primed B cells. Understanding the regulatory functions of TFH cells in the germinal center and the subsequent regulation of memory B cell responses to antigen recall represent the frontiers of this research area with the potential to alter fundamentally the design of future vaccines.
doi:10.1016/j.immuni.2009.03.003
PMCID: PMC2731675  PMID: 19303387
17.  Human Dendritic Cells Induce the Differentiation of Interleukin-21-producing T Follicular Helper-like Cells through Interleukin-12 
Immunity  2009;31(1):158-169.
Summary
T follicular helper (Tfh) cells help development of antibody responses via Interleukin-21 (IL-21). Here we show that activated human dendritic cells (DCs) induced naïve CD4+ T cells to become IL-21-producing Tfh-like cells through IL-12. CD4+ T cells primed with IL-12 induced B cells to produce immunoglobulins in a fashion dependent on IL-21 and inducible costimulator (ICOS), thus sharing fundamental characteristics with Tfh cells. The induction of Tfh-like cells by activated DCs was inhibited by neutralizing IL-12. IL-12 induced two different IL-21-producers: IL-21+IFN-γ+T-bet+ Th1 cells and IL-21+IFN-γ-T-bet- non-Th1 cells, in a manner dependent on signal transducer and activator of transcription (STAT)4. IL-12 also regulated IL-21 secretion by memory CD4+ T cells. Thus, IL-12 produced by activated DCs regulates antibody responses via developing IL-21-producing Tfh-like cells, and inducing IL-21 secretion from memory CD4+ T cells. These data suggest that the developmental pathway of Tfh cells differs between mice and humans, which have considerable implications for vaccine development.
doi:10.1016/j.immuni.2009.04.016
PMCID: PMC2731623  PMID: 19592276
18.  Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells 
Persistent virus infection drives follicular T helper cell differentiation.
CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection.
doi:10.1084/jem.20101773
PMCID: PMC3092345  PMID: 21536743
19.  IL-21 and T follicular helper cells 
International Immunology  2009;22(1):7-12.
Upon encounter with antigen, CD4+ T cells differentiate into effector Th subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important Th functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD4+ T cell subset that helps B cells is the T follicular helper (TFH) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C–X–C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. TFH cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of TFH cells. Although TFH cells have been found to produce cytokines characteristic of other Th subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated TFH function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal TFH development and function as well as in progression of autoimmune responses.
doi:10.1093/intimm/dxp112
PMCID: PMC2795365  PMID: 19933709
autoimmunity; BCL6; germinal center; Th subsets
20.  A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis 
Arthritis Research & Therapy  2012;14(6):R255.
Introduction
Interleukin (IL)-21 is a member of type I cytokine family. Recent studies indicate that IL-21 can promote T follicular helper (Tfh) cell differentiation and survival, a specialized T cell subset which provides help for B cell. It can also regulate the activation, proliferation and differentiation of human B cell and immunoglobulin (Ig) production as well as isotype switching of plasma cell. Rheumatoid arthritis (RA) is characterized by auto-antibodies overproduction such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, suggesting a pivotal role of Tfh cell and B cell in the pathogenesis of RA. This study aimed to investigate whether IL-21 had a regulatory effect on Tfh cell and B cell in RA.
Methods
Serum IL-21 concentrations were measured by ELISA. The correlations between serum IL-21 levels and clinical features of RA patients were analyzed by Spearman's rank test. The percentages of Tfh-like cells, IL-21 receptor (R) expression on Tfh-like cells and B cells in peripheral blood (PB) were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) were stimulated by rIL-21 (100 ng/ml) in the presence or absence of anti-CD40 and/or anti-IgM, and changes of IL-21R, activation-associated surface markers (CD25, CD69 and CD40), the proliferation, apoptosis and differentiation of B cells were analyzed by flow cytometry. Production of IgG and IgM in the culture supernatants was determined by ELISA.
Results
The results showed that the serum IL-21 levels in RA patients were significantly higher than that of healthy controls (HC). IL-21 concentrations were positively correlated with 28-joint count disease activity score (DAS28) and anti-CCP antibody in RA patients with high IL-21 levels. Furthermore, the frequencies of peripheral CXCR5+PD-1+CD4+ Tfh-like cells markedly increased in RA patients and the percentages of Tfh-like cells were positively correlated with DAS28 and anti-CCP antibody levels. Moreover, elevated IL-21 levels were also correlated with the frequencies of Tfh-like cells. IL-21R expression on both Tfh-like cells and B cells were significantly enhanced in RA patients. In cultures vitro, exogenous IL-21 upregulated IL-21R expression and activation-associated surface markers on B cells and promoted more B cell proliferation in RA than in HC. This IL-21-mediated effect could be reversed by IL-21R-specific neutralizing antibody. Importantly, IL-21 promoted more differentiation of B cell into plasmablast and higher levels of IgG and IgM production in RA than in HC.
Conclusions
Increased serum IL-21 levels in RA patients correlate with DAS28, anti-CCP antibody and frequencies of Tfh-like cells. IL-21 supports B cell activation, proliferation and antibody secretion via IL-21R pathway. Thus, IL-21 may be involved in the pathogenesis of RA and antagonizing IL-21 could be a novel strategy for the therapy of RA.
doi:10.1186/ar4100
PMCID: PMC3674600  PMID: 23176102
21.  Interleukin-2 inhibits germinal center formation by limiting T follicular helper differentiation 
Immunity  2012;36(5):847-856.
SUMMARY
T follicular helper (Tfh) cells promote T-dependent humoral immune responses by providing T cell help to B cells and by promoting germinal center (GC) formation and long-lived antibody responses. However, the cellular and molecular mechanisms that control Tfh differentiation in vivo are incompletely understood. Here we show that interleukin-2 (IL-2) administration impaired influenza-specific GCs, long-lived IgG responses and Tfh cells. IL-2 did not directly inhibit GC formation, but instead suppressed the differentiation of Tfh cells, thereby hindering the maintenance of influenza-specific GC B cells. Our data demonstrate that IL-2 is a critical factor that regulates successful Tfh and B cell responses in vivo and regulates Tfh cell development.
doi:10.1016/j.immuni.2012.02.012
PMCID: PMC3361521  PMID: 22464171
22.  Relapsed angioimmunoblastic T-cell lymphoma with acquired expression of CD20: a case report and review of the literature 
Background
Angioimmunoblastic T-cell lymphoma is one of the most common types of peripheral T-cell lymphomas, usually presenting at an older age with an aggressive clinical course. Its characteristic morphological presentation and follicular helper T-cell phenotype help to distinguish it from other T-cell lymphomas.
Case presentation
We recently encountered the unique case of a 63-year old patient with relapsed tumour-cell rich angioimmunoblastic T-cell lymphoma, presenting with a “classical” phenotype and, in addition, an acquired, strong, aberrant expression of CD20.
“Lineage infidelity” of phenotypic markers is a well-documented phenomenon in lymphomas and leukemias, a circumstance currently still poorly understood and with the potential to bring about erroneous interpretations, causing diagnostic havoc. This case represents one of the few documented angioimmunoblastic T-cell lymphomas with strong CD20 expression. Of interest, CD20 expression was only detected in the recurrent lymphoma and not upon initial diagnosis. The clinical importance of this finding lies in the potential for treatment with an anti-CD20 antibody, for instance Rituximab, in addition to standard chemotherapy protocols for angioimmunoblastic T-cell lymphoma.
Conclusion
Diagnostic work-up of lymphomas to determine their lineage should therefore consider morphology, pheno- as well as genotypic characteristics, where appropriate, and in particular signs of progression and change in marker profile in relapsed cases e.g. acquisition of “non-lineage” markers such as CD20 in T-cell lymphoma.
doi:10.1186/1472-6890-13-18
PMCID: PMC3680012  PMID: 23738899
Angioimmunoblastic T-cell lymphoma; Lineage infidelity; CD20; Tumour-cell rich
23.  Circulating TFH Subset Distribution Is Strongly Affected in Lupus Patients with an Active Disease 
PLoS ONE  2013;8(9):e75319.
Follicular helper T cells (TFH) represent a distinct subset of CD4+ T cells specialized in providing help to B lymphocytes, which may play a central role in autoimmune diseases having a major B cell component such as systemic lupus erythematosus. Recently, TFH subsets that share common phenotypic and functional characteristics with TFH cells from germinal centers, have been described in the peripheral blood from healthy individuals. The aim of this study was to analyze the distribution of such populations in lupus patients. Circulating TFH cell subsets were defined by multicolor flow cytometry as TFH17 (CXCR3-CCR6+), TFH1 (CXCR3 + CCR6-) or TFH2 (CXCR3-CCR6-) cells among CXCR5 + CD45RA-CD4+ T cells in the peripheral blood of 23 SLE patients and 23 sex and age-matched healthy controls. IL-21 receptor expression by B cells was analyzed by flow cytometry and the serum levels of IL-21 and Igs were determined by ELISA tests. We found that the TFH2 cell subset frequency is strongly and significantly increased in lupus patients with an active disease (SLEDAI score>8), while the TFH1 cell subset percentage is greatly decreased. The TFH2 and TFH1 cell subset frequency alteration is associated with the presence of high Ig levels and autoantibodies in patient’s sera. Moreover, the TFH2 cell subset enhancement correlates with an increased frequency of double negative memory B cells (CD27-IgD-CD19+ cells) expressing the IL-21R. Finally, we found that IgE levels in lupus patients’ sera correlate with disease activity and seem to be associated with high TFH2 cell subset frequency. In conclusion, our study describes for the first time the distribution of circulating TFH cell subsets in lupus patients. Interestingly, we found an increased frequency of TFH2 cells, which correlates with disease activity. Our results suggest that this subset might play a key role in lupus pathogenesis.
doi:10.1371/journal.pone.0075319
PMCID: PMC3777901  PMID: 24069401
24.  Helminth Protein Vaccine Induced Follicular T Helper Cell for Enhancement of Humoral Immunity against Schistosoma japonicum 
BioMed Research International  2013;2013:798164.
Protein vaccines combined with adjuvants have been widely used to induce immune responses, especially the humoral immune response, against molecular targets including parasites. Follicular T helper (Tfh) cells are the specialized providers of B-cell help, however, the induction of Tfh cells in protein vaccination has been rarely studied. Here, we report that the Schistosoma japonicum recombinant protein (SjGST-32) combined with tacrolimus (FK506) augmented the induction of Tfh cells, which expressed the canonical markers CXCR5, BCL6, and IL-21, and enhanced the humoral immune responses in BALB/c mice. Furthermore, the expression of IL-21R on germinal center (GC) B cells and memory B cells increased in immunized mice, which indicated that IL-21 from the induced Tfh cells interacted with IL-21R for activation of B cells and maintenance of long-lived humoral immunity. Our results suggest that helminth protein vaccine combined with FK506 induces Tfh cell for stimulating humoral immune responses and inducing long-lived humoral immunity.
doi:10.1155/2013/798164
PMCID: PMC3838807  PMID: 24308005
25.  MicroRNAs of the miR-17~92 family are critical regulators of TFH differentiation 
Nature immunology  2013;14(8):849-857.
T follicular helper (TFH) cells provide critical help to B cells during humoral immune responses. Here we report that mice with T cell-specific deletion of miR-17~92 family miRNAs (tKO mice) exhibited severely compromised TFH differentiation, germinal center formation, antibody responses, and failed to control chronic virus infection. Conversely, T cell-specific miR-17~92 transgenic mice spontaneously accumulated TFH cells and developed fatal immunopathology. Mechanistically, miR-17~92 family miRNAs control CD4+ T cell migration into B cell follicles by regulating ICOS-PI3K signaling intensity through suppressing the expression of the Akt phosphatase Phlpp2. These findings demonstrate that miR-17~92 family microRNAs play an essential role in TFH differentiation and establish Phlpp2 as an important mediator of their function in this process.
doi:10.1038/ni.2648
PMCID: PMC3740954  PMID: 23812097

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