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

• Published in: Journal of autoimmunity Vol. 40; pp. 28 - 44
• Main Authors: Jin, Jun-O, Han, Xiaozhe, Yu, Qing
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.02.2013; Elsevier
• Subjects: Allergy and Immunology; Animals; Antibodies; Autoimmune disease; Autoimmunity; Biological and medical sciences; CD3 Complex - immunology; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Helper cells; Homeodomain Proteins - genetics; Immune-regulatory; Inflammation; Inflammation Mediators; Interleukin 10; Interleukin 2; Interleukin 21; Interleukin 27; Interleukin 6; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-17; Interleukin-2 - metabolism; Interleukin-6 - immunology; Interleukin-6 - metabolism; Interleukins - metabolism; Intestine; Intestines - immunology; Lipopolysaccharides; Lung; Lung - immunology; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tr1 cells; Transforming growth factor- beta; Immune-regulatory; Autoimmune disease; Inflammation; Interleukin-10; Tr1 cells; Interleukin-6; Autoimmunity; Immunopathology; Cytokine; Tr1 lymphocyte; Interleukin 6; Tissue; Immunology; Interleukin 10; T-Lymphocyte
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2012.07.009

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.