Cyclin-dependent kinase 5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis

Cyclin-dependent kinase 5 (Cdk5) is a ubiquitously expressed serine/threonine kinase. However, a requirement for Cdk5 has been demonstrated only in postmitotic neurons where there is abundant expression of its activating partners p35 and/or p39. Although hyperactivation of the Cdk5–p35 complex has been found in a variety of inflammatory neurodegenerative disorders, the potential contribution of nonneuronal Cdk5–p35 activity has not been explored in this context. We describe a previously unknown function of the Cdk5–p35 complex in T cells that is required for induction of experimental autoimmune encephalomyelitis (EAE). T cell receptor (TCR) stimulation leads to a rapid induction of Cdk5–p35 expression that is required for T lymphocyte activation. Chimeric mice lacking Cdk5 gene expression in hematopoietic tissues (Cdk5−/−C) are resistant to induction of EAE, and adoptive transfer of either Cdk5−/−C or p35−/− encephalitogenic lymphocytes fails to transfer disease. Moreover, our data reveal a novel mechanism involving Cdk5-mediated phosphorylation of the actin modulator coronin 1a on threonine 418. Cdk5-deficient lymphocytes lack this posttranslational modification of coronin 1a and exhibit defective TCR-induced actin polarization and reduced migration toward CCL-19. These data define a distinct role for Cdk5 in lymphocyte biology and suggest that inhibition of this kinase may be beneficial in the treatment of T cell–mediated inflammatory disorders.

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The Innate Immune Receptor CD14 Mediates Lymphocyte Migration in EAE

Cellular Physiology and Biochemistry ◽

10.1159/000430351 ◽

2015 ◽

Vol 37 (1) ◽

pp. 269-275 ◽

Cited By ~ 6

Author(s):

Ramona Halmer ◽

Laura Davies ◽

Yang Liu ◽

Klaus Fassbender ◽

Silke Walter

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

T Cell Activation ◽

Cell Activation ◽

Innate Immune ◽

Autoimmune Encephalomyelitis ◽

Immune Receptors ◽

Experimental Autoimmune

Background: Multiple sclerosis is the most common autoimmune disease of the central nervous system in young adults and histopathologically characterized by inflammation, demyelination and gliosis. It is considered as a CD4+ T cell-mediated disease, but also a disease-promoting role of the innate immune system has been proposed, based e.g. on the observation that innate immune receptors modulate disease severity of experimental autoimmune encephalomyelitis. Recent studies of our group provided first evidence for a key role of the innate immune LPS receptor (CD14) in pathophysiology of experimental autoimmune encephalomyelitis. CD14-deficient experimental autoimmune encephalomyelitis mice showed increased clinical symptoms and enhanced infiltration of monocytes and neutrophils in brain and spinal cord. Methods: In the current study, we further investigated the causes of the disease aggravation by CD14-deficiency and examined T cell activation, also focusing on the costimulatory molecules CTLA-4 and CD28, and T cell migration capacity over the blood brain barrier by FACS analysis, in vitro adhesion and transmigration assays. Results: In the results, we observed a significantly increased migration of CD14-deficient lymphocytes across an endothelial monolayer. In contrast, we did not see any differences in expression levels of TCR/CTLA-4 or TCR/CD28 and lymphocyte adhesion to endothelial cells from CD14-deficient compared to wildtype mice. Conclusion: The results demonstrate an important role of CD14 in migration of lymphocytes, and strengthen the importance of innate immune receptors in adaptive immune disorders, such as multiple sclerosis.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.770402 ◽

2022 ◽

Vol 12 ◽

Author(s):

Lili Tang ◽

Ge Li ◽

Yang Zheng ◽

Chunmei Hou ◽

Yang Gao ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

T Cell Activation ◽

Immune Tolerance ◽

Cell Activation ◽

Autoimmune Encephalomyelitis ◽

Mhc Ii ◽

Experimental Autoimmune

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.

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