ABSTRACT
Type I IFN can exert pro- and anti-inflammatory activities in the immune system. Here, we have investigated the mechanism by which IFN-α enhances early expression of the anti-inflammatory cytokine IL-10 in human CD45RA+CD4+ T cells. With the use of transcriptomic and biochemical approaches, we found distinct and combined contributions of the IFN and the TCR signaling pathways to the induction of STAT1/2/3 and the basic leucine zipper activating transcription factor-like (BATF) family members. Moreover, IFN-induced STAT3 phosphorylation was prolonged by the TCR response, whereas IFN-induced STAT2 phosphorylation was of long duration. With the use of RNA interference (RNAi), we identified STAT3 as the major actor and STAT2 as a contributor of the IFN action on IL-10 Upon TCR/IFN costimulation, STAT3 directly bound at the IL-10 conserved noncoding sequence (CNS)- 9, an enhancer element known to recruit BATF in CD4 T cells. The cosilencing of the 3 BATFs resulted in an overall reduction of IL-10 expression, but the promoting activity of IFN-α was retained. These results support the notion that the IFN action is indexed on BATF function and provide evidence for a cooperation between BATFs and STAT3, the latter being activated via early IFN and delayed TCR effects.
Subject(s)
Basic-Leucine Zipper Transcription Factors/immunology , CD4-Positive T-Lymphocytes/drug effects , Interferon-alpha/pharmacology , Interleukin-10/immunology , STAT2 Transcription Factor/immunology , STAT3 Transcription Factor/immunology , Antibodies/pharmacology , Basic-Leucine Zipper Transcription Factors/antagonists & inhibitors , Basic-Leucine Zipper Transcription Factors/genetics , Binding Sites , CD28 Antigens/antagonists & inhibitors , CD28 Antigens/genetics , CD28 Antigens/immunology , CD3 Complex/genetics , CD3 Complex/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Cycloheximide/pharmacology , Enhancer Elements, Genetic , Gene Expression Regulation , Humans , Interferon-alpha/immunology , Interleukin-10/genetics , Phosphorylation/drug effects , Primary Cell Culture , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/immunology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , STAT1 Transcription Factor/antagonists & inhibitors , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/immunology , STAT2 Transcription Factor/antagonists & inhibitors , STAT2 Transcription Factor/genetics , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/genetics , Signal TransductionABSTRACT
Interleukin (IL)-4 and IL-13 are T helper 2 cytokines whose biological functions are induced through a common IL-4 receptor alpha chain (IL-4Ralpha). CD4(+) T cell-specific IL-4Ralpha-mediated signaling drives susceptibility to Leishmania major infection, but is not essential to host survival following Schistosoma mansoni infection. Here we generated a novel mouse model lacking IL-4Ralpha expression specifically on all T cells (iLck(cre)Il4ra(-/lox)), which was compared with CD4(+) T cell-specific IL-4Ralpha-deficient mice (Lck(cre)Il4ra(-/lox)), to investigate the possible roles of IL-4Ralpha responsive non-CD4(+) T cells during either L. major or S. mansoni infection. Our results demonstrate a successful generation of transgene-bearing hemizygous iLck(cre)Il4ra(-/lox) BALB/c mice that have effective deletion of IL-4Ralpha on all T-cell populations. We show that iLck(cre)Il4ra(-/lox) mice infected with L. major developed a healing disease phenotype as previously observed in Lck(cre)Il4ra(-/lox) mice, demonstrating that absence of IL-4Ralpha-responsive non-CD4(+) in addition to CD4(+) T cells does not further affect transformation of BALB/c to a healer phenotype. In acute schistosomiasis, however, iLck(cre)Il4ra(-/lox) mice showed enhanced mortality compared with Il4ra(-/lox) and Lck(cre)Il4ra(-/lox) mice. iLck(cre)Il4ra(-/lox) mice died with similar kinetics to highly susceptible Il4ra(-/-) mice, despite controlling gut inflammation. In addition, iLck(cre)Il4ra(-/lox) mice presented increased liver granuloma sizes, as compared with Lck(cre)Il4ra(-/lox) mice, with similar eosinophils, fibrosis, and liver damage. In conclusion, IL-4Ralpha-responsive non-CD4(+) T cells prolong survival to acute schistosomiasis and contribute to the better control of hepatic granulomatous inflammation.
