Abstract
Tim-3, an immune checkpoint inhibitor, is widely expressed on the immune cells and contributes to immune tolerance. However, the mechanisms by which Tim-3 induces immune tolerance remain to be determined. Major histocompatibility complex II (MHC-II) plays a key role in antigen presentation and CD4+T cell activation. Dysregulated expressions of Tim-3 and MHC-II are associated with the pathogenesis of many autoimmune diseases including multiple sclerosis. Here we demonstrated that, by suppressing MHC-II expression in macrophages via the STAT1/CIITA pathway, Tim-3 inhibits MHC-II-mediated autoantigen presentation and CD4+T cell activation. As a result, overexpression or blockade of Tim-3 signaling in mice with experimental autoimmune encephalomyelitis (EAE) inhibited or increased MHC-II expression respectively and finally altered clinical outcomes. We thus identified a new mechanism by which Tim-3 induces immune tolerance in vivo and regulating the Tim-3-MHC-II signaling pathway is expected to provide a new solution for multiple sclerosis treatment.
Highlights
Tcell immunoglobulin mucin domain 3 (Tim-3) is widely expressed on the surface of many immune cells including T cells and macrophages [1, 2]
The Major histocompatibility complex II (MHC-II) expression in Tim-3-KO mice was increased in macrophages compared with wild-type C57BL/6 mice (WT) mice (Figure 1C), and MHC-II expression was decreased in macrophages from Tim-3-TG mice compared with WT mice (Figure 1D)
The 67 healthy individual samples were analyzed and showed an inverse correlation (r = -0.2458, p = 0.0450) between the expression of Tim-3 and MHC-II (HLA-DR) in CD14+ monocytes/macrophages (Figure 1G). These results suggest that Tim-3 signaling inhibited MHC-II expression in mouse macrophages and in human macrophages
Summary
Tcell immunoglobulin mucin domain 3 (Tim-3) is widely expressed on the surface of many immune cells including T cells and macrophages [1, 2]. As an immune checkpoint inhibitor, Tim-3 contributes to immune tolerance by inducing T cell apoptosis or by suppressing the activation of innate immune cells [1, 3]. Our findings and other reports showed that Tim-3 may control T cell response indirectly via regulating the function of innate immune cells [1, 3, 7]. The mechanism by which Tim-3 mediates immune tolerance, especially innate immune tolerance, remains largely unclear.
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