New insights into the differentiation and function of T follicular helper cells

The seminal studies characterizing T follicular helper (TFH) cells described a non-polarized CD4+ T cell population with a unique ability to home to B cell follicles and to induce antibody production by B cells. In the past few years, the study of TFH cells has enjoyed a renaissance and there has been a surge of research activity aimed at understanding the function and differentiation of these important cells. This Review focuses on the current progress in TFH cell biology and the important questions that remain unanswered. Particular attention is paid to recent studies that support the idea that TFH cells are a separate T cell lineage and those that probe the relationship of TFH cells to other T helper cell subsets.

[1]  E. Butcher,et al.  Subspecialization of Cxcr5+ T Cells , 2001, The Journal of experimental medicine.

[2]  Yuka Kanno,et al.  Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. , 2009, Immunity.

[3]  Federica Sallusto,et al.  Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production , 2000, The Journal of experimental medicine.

[4]  R. Zinkernagel,et al.  Immunological Memory , 2006 .

[5]  Hai Qi,et al.  SLAM receptors and SAP influence lymphocyte interactions, development and function , 2009, Nature Reviews Immunology.

[6]  A. Plebani,et al.  ICOS Deficiency Is Associated with a Severe Reduction of CXCR5+CD4 Germinal Center Th Cells1 , 2006, The Journal of Immunology.

[7]  T. Winkler,et al.  Activation of Virus-specific Memory B Cells in the Absence of T Cell Help , 2004, The Journal of experimental medicine.

[8]  Robert W. Williams,et al.  Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice , 2008, Nature Immunology.

[9]  G. Freeman,et al.  Programmed Death-1 (PD-1) is a Marker of Germinal Center-associated T Cells and Angioimmunoblastic T-Cell Lymphoma , 2006, The American journal of surgical pathology.

[10]  P. Hodgkin,et al.  Decision criteria for resolving isotype switching conflicts by B cells , 2005, European journal of immunology.

[11]  A. Dogan,et al.  Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified , 2006, Modern Pathology.

[12]  J. Banchereau,et al.  The CD40 antigen and its ligand. , 1994, Annual review of immunology.

[13]  P. Scott,et al.  Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites , 2004, Nature Medicine.

[14]  A. D. Panopoulos,et al.  Essential autocrine regulation by IL-21 in the generation of inflammatory T cells , 2007, Nature.

[15]  Michael L. Dustin,et al.  In vivo imaging of germinal centres reveals a dynamic open structure , 2007, Nature.

[16]  K. Toellner,et al.  T Helper 1 (th1) and Th2 Characteristics Start to Develop during T Cell Priming and Are Associated with an Immediate Ability to Induce Immunoglobulin Class Switching , 1998 .

[17]  D. Littman,et al.  The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt , 2008, Nature Immunology.

[18]  M. Kikuchi,et al.  Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma. , 1999, Human pathology.

[19]  Keiichiro Suzuki,et al.  Preferential Generation of Follicular B Helper T Cells from Foxp3+ T Cells in Gut Peyer's Patches , 2009, Science.

[20]  D. Metz,et al.  B7RP-1 Blockade Ameliorates Autoimmunity through Regulation of Follicular Helper T Cells , 2009, The Journal of Immunology.

[21]  J. Banchereau,et al.  Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. , 1996, Immunity.

[22]  M. Neuberger,et al.  Affinity dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate. , 1998, Immunity.

[23]  J. Cyster,et al.  Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1High Germinal Center-Associated Subpopulation1 , 2007, The Journal of Immunology.

[24]  C. Mackay,et al.  The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. , 2009, Immunity.

[25]  Terry B. Strom,et al.  IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells , 2007, Nature.

[26]  I. Maclennan,et al.  Maturation and Dispersal of B‐Cell Clones during T Cell‐Dependent Antibody Responses , 1992, Immunological reviews.

[27]  T. Dörner,et al.  Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. , 2004, Arthritis and rheumatism.

[28]  T. Pawson,et al.  ICOS is essential for effective T-helper-cell responses , 2001, Nature.

[29]  Andreas Hutloff,et al.  ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 , 1999, Nature.

[30]  E. Butcher,et al.  Unique gene expression program of human germinal center T helper cells. , 2004, Blood.

[31]  A. Banham,et al.  Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells1 , 2005, The Journal of Immunology.

[32]  M. Kurrer,et al.  IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. , 2007, Blood.

[33]  Mark J. Miller,et al.  Antigen-Engaged B Cells Undergo Chemotaxis toward the T Zone and Form Motile Conjugates with Helper T Cells , 2005, PLoS biology.

[34]  A. Satoskar,et al.  Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells , 2002, The Journal of experimental medicine.

[35]  H. Rahn,et al.  Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression , 2006, European journal of immunology.

[36]  J. Bajorath,et al.  The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome , 1993, Cell.

[37]  C. Mackay,et al.  T Follicular Helper Cells Express a Distinctive Transcriptional Profile, Reflecting Their Role as Non-Th1/Th2 Effector Cells That Provide Help for B Cells1 , 2004, The Journal of Immunology.

[38]  M. Piris,et al.  Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres: a neoplasia with origin in the outer zone of the germinal centre? Clinicopathological and immunohistochemical study of 10 cases with follicular T-cell markers , 2009, Modern Pathology.

[39]  M. Hegen,et al.  Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. , 2007, Arthritis and rheumatism.

[40]  Christoph Wilhelm,et al.  Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset , 2008, Nature Immunology.

[41]  K. Rajewsky,et al.  Persistence of memory B cells in mice deprived of T cell help. , 1990, International immunology.

[42]  J. Cyster,et al.  Germinal-center organization and cellular dynamics. , 2007, Immunity.

[43]  John T. Chang,et al.  Asymmetric T Lymphocyte Division in the Initiation of Adaptive Immune Responses , 2007, Science.

[44]  E. Kremmer,et al.  Expression of the G-protein--coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. , 1994, Blood.

[45]  L. Glimcher,et al.  The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. , 1999, Immunity.

[46]  P. Lipsky,et al.  Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. , 2003, The Journal of clinical investigation.

[47]  K. Murphy,et al.  The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model , 1995, The Journal of experimental medicine.

[48]  D. Levy,et al.  IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways , 2007, Nature Immunology.

[49]  T. L. Collins,et al.  Heterogeneity of helper/inducer T lymphocytes. IV. Stimulation of resting and activated B cells by Th1 and Th2 clones. , 1990, Journal of immunology.

[50]  E. Butcher,et al.  Subspecialization of CXCR 5 T Cells : B Helper Activity Is Focused in a Germinal Center – localized Subset of CXCR 5 T Cells , 2001 .

[51]  Quanzhen Li,et al.  A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[52]  S. Tangye,et al.  Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-211 , 2006, The Journal of Immunology.

[53]  E. Wolf,et al.  A Putative Chemokine Receptor, BLR1, Directs B Cell Migration to Defined Lymphoid Organs and Specific Anatomic Compartments of the Spleen , 1996, Cell.

[54]  A. Gulbranson‐Judge,et al.  Sequential antigen‐specific growth of T cells in the T zones and follicles in response to pigeon cytochrome c , 1996, European journal of immunology.

[55]  Y. Li,et al.  Cytokine-Mediated Regulation of Human B Cell Differentiation into Ig-Secreting Cells: Predominant Role of IL-21 Produced by CXCR5+ T Follicular Helper Cells1 , 2007, The Journal of Immunology.

[56]  T. Wynn,et al.  The IL-21 receptor augments Th2 effector function and alternative macrophage activation. , 2006, The Journal of clinical investigation.

[57]  N. Miyasaka,et al.  Involvement of Inducible Costimulator-B7 Homologous Protein Costimulatory Pathway in Murine Lupus Nephritis 1 , 2003, The Journal of Immunology.

[58]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[59]  Burton E. Barnett,et al.  Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation , 2009, Science.

[60]  K. Toellner,et al.  Th2 Activities Induced During Virgin T Cell Priming in the Absence of IL-4, IL-13, and B Cells1 , 2002, The Journal of Immunology.

[61]  G. Kelsoe,et al.  Spontaneous formation of germinal centers in autoimmune mice , 2001, Journal of leukocyte biology.

[62]  I. Maclennan,et al.  Germinal Centers without T Cells , 2000, The Journal of experimental medicine.

[63]  Y. Takasaki,et al.  Striking alteration of some populations of T/B cells in systemic lupus erythematosus: relationship to expression of CD62L or some chemokine receptors , 2008, Lupus.

[64]  P. Schaerli,et al.  Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells. , 2006, Blood.

[65]  Antonio Lanzavecchia,et al.  Chemokine Receptor Expression Identifies Pre–T Helper (Th)1, Pre–Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells , 2004, The Journal of experimental medicine.

[66]  N. Harris,et al.  Peripheral T-Cell Lymphoma With Follicular Involvement and a CD4+/bcl-6+ Phenotype , 2001, The American journal of surgical pathology.

[67]  S. Tangye,et al.  IL-21-Induced Isotype Switching to IgG and IgA by Human Naive B Cells Is Differentially Regulated by IL-41 , 2008, The Journal of Immunology.

[68]  R. Locksley,et al.  Cytokine-secreting follicular T cells shape the antibody repertoire , 2009, Nature Immunology.

[69]  W. Leonard,et al.  Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. , 2009, Blood.

[70]  R. Brink,et al.  The germinal center reaction. , 2010, The Journal of allergy and clinical immunology.

[71]  Juan Ma,et al.  The Role of ICOS in the CXCR5+ Follicular B Helper T Cell Maintenance In Vivo1 , 2005, The Journal of Immunology.

[72]  M. Grusby,et al.  IL-21 Inhibits IFN-γ Production in Developing Th1 Cells through the Repression of Eomesodermin Expression1 , 2006, The Journal of Immunology.

[73]  J. Banchereau,et al.  Functions of CD40 on B cells, dendritic cells and other cells. , 1997, Current opinion in immunology.

[74]  R. Nurieva,et al.  Bcl6 Mediates the Development of T Follicular Helper Cells , 2009, Science.

[75]  D. Littman,et al.  Plasticity of CD4+ T cell lineage differentiation. , 2009, Immunity.

[76]  C. Mackay,et al.  A fundamental role for interleukin-21 in the generation of T follicular helper cells. , 2008, Immunity.

[77]  Lisa M. Ebert,et al.  B cells alter the phenotype and function of follicular‐homing CXCR5+ T cells , 2004, European journal of immunology.

[78]  M. Cook,et al.  Follicular helper T cells are required for systemic autoimmunity , 2009, The Journal of experimental medicine.

[79]  Irah L. King,et al.  IL-4–producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells , 2009, The Journal of experimental medicine.

[80]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[81]  P. Loetscher,et al.  Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function , 2000, The Journal of experimental medicine.

[82]  B. Zheng,et al.  Human germinal center T cells are unique Th cells with high propensity for apoptosis induction. , 2006, International immunology.

[83]  Xiaojing Ma.  Faculty Opinions recommendation of Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. , 2009 .

[84]  A. Fischer,et al.  CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM , 1993, Nature.

[85]  Andreas Radbruch,et al.  Expression of ICOS In Vivo Defines CD4+ Effector T Cells with High Inflammatory Potential and a Strong Bias for Secretion of Interleukin 10 , 2003, The Journal of experimental medicine.

[86]  D. Dorfman,et al.  Germinal-center T-helper-cell markers PD-1 and CXCL13 are both expressed by neoplastic cells in angioimmunoblastic T-cell lymphoma. , 2009, American journal of clinical pathology.

[87]  Lisa M. Toney,et al.  Inhibition of Th2 Differentiation and GATA-3 Expression by BCL-6 1 , 2003, The Journal of Immunology.

[88]  P. Lipsky,et al.  IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells1 , 2005, The Journal of Immunology.

[89]  K. Calame,et al.  Blimp-1 Attenuates Th1 Differentiation by Repression of ifng, tbx21, and bcl6 Gene Expression , 2008, The Journal of Immunology.

[90]  P. Lane,et al.  Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5–Positive Cd4 Cells and Germinal Centers , 1999, The Journal of experimental medicine.

[91]  V. Kuchroo,et al.  IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3− effector T cells , 2008, Nature Immunology.

[92]  D. R. Taylor,et al.  Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation , 1996, The Journal of experimental medicine.

[93]  D. Altmann,et al.  Is selection for TCR affinity a factor in cytokine polarization? , 2002, Trends in immunology.

[94]  A. Schäffer,et al.  Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency , 2003, Nature Immunology.

[95]  D. Hwang,et al.  Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. , 2008, Immunity.

[96]  V. Kuchroo,et al.  The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells , 2009, Nature Immunology.

[97]  Irah L. King,et al.  T follicular helper cells differentiate from Th2 cells in response to helminth antigens , 2009, The Journal of experimental medicine.

[98]  R. Copley,et al.  A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity , 2005, Nature.

[99]  J. Schölmerich,et al.  OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice , 2003, European journal of immunology.

[100]  P. Hillsamer,et al.  Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. , 2004, The Journal of clinical investigation.

[101]  M. Collins,et al.  IL-21 Has a Pathogenic Role in a Lupus-Prone Mouse Model and Its Blockade with IL-21R.Fc Reduces Disease Progression , 2007, The Journal of Immunology.

[102]  J. Cyster,et al.  In Vivo–Activated Cd4 T Cells Upregulate Cxc Chemokine Receptor 5 and Reprogram Their Response to Lymphoid Chemokines , 1999, The Journal of experimental medicine.

[103]  R. Zinkernagel,et al.  CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4+ T cell functions , 1996, The Journal of experimental medicine.

[104]  C. Mackay,et al.  T follicular helper (TFH) cells in normal and dysregulated immune responses. , 2008, Annual review of immunology.

[105]  K. Fuller,et al.  T cells within germinal centers are specific for the immunizing antigen. , 1993, Journal of immunology.

[106]  A. Dogan,et al.  Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified , 2007, Modern Pathology.

[107]  H. Claman,et al.  Thymus-Marrow Cell Combinations. Synergism in Antibody Production.∗ , 1966, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[108]  K. Toellner,et al.  The changing preference of T and B cells for partners as T‐dependent antibody responses develop , 1997, Immunological reviews.

[109]  F. Klauschen,et al.  SAP-controlled T-B cell interactions underlie germinal centre formation , 2008, Nature.

[110]  S. Pai,et al.  GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[111]  N. Fazilleau,et al.  The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding , 2009, Nature Immunology.

[112]  W. Leonard,et al.  A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice , 2009, Proceedings of the National Academy of Sciences.

[113]  L. Notarangelo,et al.  Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM , 1993, Nature.

[114]  M. Hatano,et al.  Disruption of the Bcl6 Gene Results in an Impaired Germinal Center Formation , 1997, The Journal of experimental medicine.

[115]  E. Ingulli,et al.  Visualization of specific B and T lymphocyte interactions in the lymph node. , 1998, Science.

[116]  N. Fazilleau,et al.  Lymphoid reservoirs of antigen-specific memory T helper cells , 2007, Nature Immunology.

[117]  F. Brombacher,et al.  Immune Responses of IL‐4, IL‐5, IL‐6 Deficient Mice , 1995, Immunological reviews.

[118]  E. Campo,et al.  Primary Cutaneous CD4+ Small/Medium-sized Pleomorphic T-cell Lymphoma Expresses Follicular T-cell Markers , 2009, The American journal of surgical pathology.

[119]  V. Kuchroo,et al.  Cutting Edge: IL-27 Induces the Transcription Factor c-Maf, Cytokine IL-21, and the Costimulatory Receptor ICOS that Coordinately Act Together to Promote Differentiation of IL-10-Producing Tr1 Cells1 , 2009, The Journal of Immunology.

[120]  Jason G. Cyster,et al.  Imaging of Germinal Center Selection Events During Affinity Maturation , 2007, Science.

[121]  P. Gaulard,et al.  Molecular classification of T-cell lymphomas. , 2009, Critical reviews in oncology/hematology.

[122]  Naděžda Brdičková,et al.  CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs , 2006, Nature.

[123]  G. Freeman,et al.  Restoring function in exhausted CD8 T cells during chronic viral infection , 2006, Nature.