Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities.

The conditions leading to the activation/differentiation of T-helper (Th) cells dedicated for B-cell antibody production are still poorly characterized. We now demonstrate that interleukin-6 (IL-6) promotes the differentiation of naive T lymphocytes into helper cells able to promote B-cell activation and antibody secretion. IL-6-driven acquisition of B-cell help capacity requires expression of the signal transducer and activator of transcription 3 (STAT3), but not STAT4 or STAT6 transcription factors, suggesting that the ability to provide help to B cells is not restricted to a well-defined Th1 or Th2 effector population. T cell-specific STAT3-deficient mice displayed reduced humoral responses in vivo that could not be related to an altered expansion of CXCR5-expressing helper T cells. IL-6 was shown to promote IL-21 secretion, a cytokine that was similarly found to promote the differentiation of naive T cells into potent B-cell helper cells. Collectively, these data indicate that the ability to provide B-cell help is regulated by IL-6/IL-21 through STAT3 activation, independently of Th1, Th2, Th17, or follicular helper T cell (T(FH)) differentiation.

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

[2]  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.

[3]  Jay K Kolls,et al.  The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation , 2022 .

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

[5]  T. Macdonald,et al.  Autocrine Regulation of IL-21 Production in Human T Lymphocytes1 , 2008, The Journal of Immunology.

[6]  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.

[7]  Lai Wei,et al.  IL-21 Is Produced by Th17 Cells and Drives IL-17 Production in a STAT3-dependent Manner* , 2007, Journal of Biological Chemistry.

[8]  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.

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

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

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

[12]  F. Andris,et al.  CD4+CD25+ regulatory T cells control the magnitude ofT‐dependent humoral immune responses to exogenous antigens , 2006, European journal of immunology.

[13]  M. Nussenzweig,et al.  Inducing and expanding regulatory T cell populations by foreign antigen , 2005, Nature Immunology.

[14]  W. Leonard,et al.  Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation , 2005, Nature Reviews Immunology.

[15]  M. Grusby,et al.  Biology of IL‐21 and the IL‐21 receptor , 2004, Immunological reviews.

[16]  K. Smith,et al.  In Vivo Generated Th1 Cells Can Migrate to B Cell Follicles to Support B Cell Responses1 , 2004, The Journal of Immunology.

[17]  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.

[18]  M. Moser,et al.  Depending on their maturation state, splenic dendritic cells induce the differentiation of CD4+ T lymphocytes into memory and/or effector cells in vivo , 2004, European journal of immunology.

[19]  S. Szabo,et al.  Molecular mechanisms regulating Th1 immune responses. , 2003, Annual review of immunology.

[20]  G. Trinchieri,et al.  The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. , 2003, Immunity.

[21]  K. Toellner,et al.  Extrafollicular antibody responses , 2003, Immunological reviews.

[22]  M. Dullaers,et al.  Lentivirally transduced dendritic cells as a tool for cancer immunotherapy , 2003, The journal of gene medicine.

[23]  A. Sher,et al.  A Critical Role for IL-21 in Regulating Immunoglobulin Production , 2002, Science.

[24]  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.

[25]  C. Snapper,et al.  Endogenous Pro- and Anti-Inflammatory Cytokines Differentially Regulate an In Vivo Humoral Response to Streptococcus pneumoniae , 2002, Infection and Immunity.

[26]  E. Butcher,et al.  Separable effector T cell populations specialized for B cell help or tissue inflammation , 2001, Nature Immunology.

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

[28]  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.

[29]  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.

[30]  L. Glimcher,et al.  Lineage commitment in the immune system: the T helper lymphocyte grows up. , 2000, Genes & development.

[31]  L. Ailles,et al.  Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences , 2000, Nature Genetics.

[32]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[33]  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.

[34]  Dexi Liu,et al.  Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA , 1999, Gene Therapy.

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

[36]  G. Klaus,et al.  CD28 co-stimulation stabilizes the expression of the CD40 ligand on T cells. , 1998, International immunology.

[37]  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 .

[38]  A. O’Garra,et al.  Cytokines induce the development of functionally heterogeneous T helper cell subsets. , 1998, Immunity.

[39]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[40]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[41]  W. Paul,et al.  Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene , 1996, Nature.

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

[43]  R. Fernandez-Botran,et al.  Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells , 1988, Nature.

[44]  J. Renauld,et al.  cDNA cloning of murine interleukin‐HP1: homology with human interleukin 6 , 1988, European journal of immunology.

[45]  D. Littman,et al.  The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. , 2006, Cell.