Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation

Abstract

Compared with its pro-inflammatory function, the mechanisms underlying the anti-inflammatory effect of IL-6 are poorly understood. IL-6 can cooperate with TGF-β to induce IL-10 production in Th17 cells in vitro. However, the effect of IL-6 on generation of Tr1 cells and the in vivo importance of this effect are mostly uncharacterized. In this study, we showed that in vitro, IL-6 can induce the generation of IL-10-producing Tr1 cells from naïve CD4 T cells, independently of IL-27 and TGF-β. IL-6 induces IL-21 production in CD4 T cells and IL-10-inducing effect of IL-6 requires both IL-21 and IL-2. Although IL-6 cannot induce IL-10 production in CD8 T cells in a cell-autonomous manner, it can do so indirectly through promoting CD4 T cell IL-21 production. The IL-10-producing T cells induced by IL-6 have phenotypic, genetic and functional traits of Tr1 cells and can suppress LPS-induced in vivo inflammatory response in an IL-10-dependent fashion. Blockade of IL-6 in two autoimmune inflammation models, induced respectively by anti-CD3 antibody or Treg-depletion, led to reduction in IL-10-producing T cells and exacerbated inflammation of lung and intestine. Thus, we delineated critical pathways involved in IL-6-induced generation of Tr1 cells and demonstrated the importance of this event in restraining autoimmune tissue inflammation.

Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance

“…13,[20][21][22] In mouse CD4 1 T cells, IL-6-associated signaling resulted in an evident increase of IL-10 mRNA levels in an IL-2-and IL-21-dependent pattern. 20 At the molecular level, IL-6 signaling drives expression of c-Maf, AhR, and IRF4, all of which are crucial transcription factors for IL-10 secretion and Tr1 cellular differentiation. 20 Furthermore, it has been demonstrated that the transcriptional effects of IL-6 and IL-2 are mediated by the signal transducer and activator of transcription 3 (STAT3) and STAT5, respectively.…”

“…20 At the molecular level, IL-6 signaling drives expression of c-Maf, AhR, and IRF4, all of which are crucial transcription factors for IL-10 secretion and Tr1 cellular differentiation. 20 Furthermore, it has been demonstrated that the transcriptional effects of IL-6 and IL-2 are mediated by the signal transducer and activator of transcription 3 (STAT3) and STAT5, respectively. 20 Activated STAT3 and STAT5 can both directly bind to Il10 and c-Maf promoters; thus, combined STAT5 and STAT3 activities might optimally activate these promoters and those of Ahr and IRF4.…”

“…20 Furthermore, it has been demonstrated that the transcriptional effects of IL-6 and IL-2 are mediated by the signal transducer and activator of transcription 3 (STAT3) and STAT5, respectively. 20 Activated STAT3 and STAT5 can both directly bind to Il10 and c-Maf promoters; thus, combined STAT5 and STAT3 activities might optimally activate these promoters and those of Ahr and IRF4. 20,[23][24][25][26] Moreover, ROG is a transcriptional factor associated with Tr1 cells in mice.…”

“…20 Activated STAT3 and STAT5 can both directly bind to Il10 and c-Maf promoters; thus, combined STAT5 and STAT3 activities might optimally activate these promoters and those of Ahr and IRF4. 20,[23][24][25][26] Moreover, ROG is a transcriptional factor associated with Tr1 cells in mice. 13 However, ROG is not specific for Tr1 cells, as it is rapidly induced in other T helper (Th) cells upon activation.…”

“…31 Second, many studies have reported that cytokines are also essential to Tr1-cell induction, such as IL-21, IL-6, IL-27, and especially IL-10. 20,26,30,31 Third, co-stimulatory molecules such as ICOS ligand (ICOS-L), CD46, CD2, and CD55 are involved in the differentiation of Tr1 cells. 30,[32][33][34] It has also been showed that the long-term interactions of GITR/GITRL signaling boosted Tr1-cell differentiation and expansion in mice in vivo.…”