ABSTRACT
The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen-loaded, IL-6-deficient DCs to naïve mice induced an exacerbated Th2 response, characterized by the differentiation of GATA-3-expressing T lymphocytes secreting high levels of IL-4, IL-5, and IL-13. Coinjection of wild type and IL-6-deficient bone marrow-derived dendritic cells (BMDCs) confirmed that IL-6 exerted a dominant, negative influence on Th2-cell development. This finding was confirmed in vitro, where exogenously added IL-6 was found to limit IL-4-induced Th2-cell differentiation. iNKT cells were required for optimal Th2-cell differentiation in vivo although their activation occurred independently of IL-6 secretion by the BMDCs. Collectively, these observations identify IL-6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity.
Subject(s)
Dendritic Cells/immunology , Interleukin-6/immunology , Th2 Cells/cytology , Animals , Asthma/immunology , Basophils/immunology , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Cell Differentiation , Dendritic Cells/cytology , Dendritic Cells/transplantation , GATA3 Transcription Factor/biosynthesis , Interleukin-13/metabolism , Interleukin-4/metabolism , Interleukin-5/metabolism , Interleukin-6/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Natural Killer T-Cells/immunology , Ovalbumin , Th2 Cells/immunologyABSTRACT
The generation of high-affinity antibodies and the development of B cell memory are dependent on the help provided by CD4 T cells. Mouse studies indicate that STAT3 signaling in CD4 T cells promotes the acquisition of the B cell help function. However, the role of STAT3 in humans has been controversial. In this study, we show that IL-6 and other STAT3 activating cytokines (IL-21 and IL-27) induce the differentiation of CD4 T cells promoting antibody production by B cells. The acquisition of B cell stimulating properties by naive cord blood CD4 T cells required the STAT3-dependent expression of ICOS and IL-21. Gene reporter and ChIP experiments unambiguously demonstrated that upon IL-6 stimulation, STAT3 induces the transcription of the ICOS gene through direct recruitment to the proximal promoter region indicating that STAT3 acts in part through the direct activation of the ICOS gene.
Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Inducible T-Cell Co-Stimulator Protein/immunology , Interleukin-6/immunology , STAT3 Transcription Factor/immunology , Animals , Antibody Formation , B-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation , Cells, Cultured , Humans , Inducible T-Cell Co-Stimulator Protein/genetics , Interleukin-12/immunology , Interleukin-27/immunology , Lymphocyte Activation , Mice , Signal Transduction , Transcriptional ActivationABSTRACT
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.
Subject(s)
B-Lymphocytes/immunology , Cell Differentiation , Interleukin-6/physiology , STAT3 Transcription Factor/physiology , T-Lymphocytes, Helper-Inducer/physiology , T-Lymphocytes/physiology , Animals , Antibody Formation/drug effects , Antibody Formation/genetics , B-Lymphocytes/drug effects , Cell Differentiation/immunology , Interleukin-6/genetics , Interleukin-6/pharmacology , Interleukins/metabolism , Interleukins/physiology , Lymphocyte Activation/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, CXCR5/metabolism , STAT3 Transcription Factor/genetics , Signal Transduction/genetics , Signal Transduction/physiology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes, Helper-Inducer/immunologyABSTRACT
CD4+ CD25+ T reg cells are critical for peripheral tolerance and prevention of autoimmunity. Here we show that CD4+ CD25+ T reg also regulate the magnitude of humoral responses against a panel of T-dependent antigens of foreign origin during both primary and secondary immune responses. Depletion of CD4+ CD25+ T cells leads to increased antigen-specific antibody production and affinity maturation but does not affect T-independent B cell responses, suggesting that CD4+ CD25+ T reg exert a feedback mechanism on non-self antigen-specific antibody secretion by dampening the T cell help for B cell activation. Moreover, we show that CD4+ CD25+ T reg also suppress in vitro B cell immunoglobulin production by inhibiting CD4+ CD25- T cell help delivery, and that blockade of TGF-beta activity abolishes this suppression.