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Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II.

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.

SUBMITTER: Tang L

PROVIDER: S-EPMC8793033 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II.

Tang Lili L Li Ge G Zheng Yang Y Hou Chunmei C Gao Yang Y Hao Ying Y Gao Zhenfang Z Mo Rongliang R Li Yuxiang Y Shen Beifen B Wang Renxi R Wang Zhiding Z Han Gencheng G

Frontiers in immunology 20220113

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<sup>+</sup>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 s ...[more]

PMID: 35095844

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Project description:BackgroundExperimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE.MethodsC57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis.ResultsHere, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55 immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1-/+ mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+ EAE mice.ConclusionsThe present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination.

Project description:BackgroundActivated protein C (APC), a serine protease with antithrombotic effects, protects in animal models of ischemic stroke by suppressing inflammation and enhancing vascular integrity, angiogenesis, neurogenesis and neuroprotection. A small number of animal studies suggest it might also have therapeutic potential in multiple sclerosis (MS), though results have been mixed. Based on these conflicting data, the goals of this study were to clarify the therapeutic potential of APC in the experimental autoimmune encephalomyelitis (EAE) model of MS and to determine mechanistically how APC mediates this protective effect.MethodsThe protective potential of APC was examined in a chronic progressive model of EAE. Vascular breakdown, tight junction protein expression and vascular expression of fibronectin and α5β1 integrin as well as vascularity and glial activation were analyzed using immunofluorescence (IF) of spinal cord sections taken from mice with established EAE. The direct influence of APC on microglial activation was evaluated in vitro by a combination of morphology and MMP-9 expression.ResultsAPC attenuated the progression of EAE, and this was strongly associated at the histopathological level with reduced levels of leukocyte infiltration and concomitant demyelination. Further analysis revealed that APC reduced vascular breakdown which was associated with maintained endothelial expression of the tight junction protein zonula occludens-1 (ZO-1). In addition, APC suppressed microglial activation in this EAE model and in vitro studies revealed that APC strongly inhibited microglial activation at both the morphological level and by the expression of the pro-inflammatory protease MMP-9.ConclusionThese findings build on the work of others in demonstrating strong therapeutic potential for APC in the treatment of inflammatory demyelinating disease and suggest that enhancement of vascular integrity and suppression of microglial activation may be important mediators of this protection.

Dataset Information

Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II.

Publications

Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II.

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