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CD5-CK2 Binding/Activation-Deficient Mice Are Resistant to Experimental Autoimmune Encephalomyelitis: Protection Is Associated with Diminished Populations of IL-17-Expressing T Cells in the Central Nervous System¹

Robert C. Axtell^*,, Liang Xu^*, Scott R. Barnum and Chander Raman^2,*

^* Department of Medicine and Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294

Regulating the differentiation and persistence of encephalitogenic T cells is critical for the development of experimental autoimmune encephalomyelitis (EAE). We reported recently that CD5 has an engagement-dependent prosurvival activity in T cells that played a direct role in the induction and progression EAE. We predicted that CD5 regulates T cell apoptosis/survival through the activation of CK2, a prosurvival serine/threonine kinase that associates with the receptor. To test this hypothesis, we generated mice expressing CD5 with the inability to bind and activate CK2 and assessed their susceptibility to EAE. We found mice deficient in CD5-CK2 signaling pathway were mostly resistant to the development of EAE. Resistance to EAE was associated with a dramatic decrease in a population of effector infiltrating Th cells that coexpress IFN- and IL-17 and, to a lesser extent, cells that express IFN- or IL-17 in draining lymph nodes and spinal cords. We further show that T cells deficient in CD5-CK2 signaling hyperproliferate following primary stimulation; however, following restimulation, they rapidly develop nonresponsiveness and exhibit elevated activation-induced cell death. Our results provide a direct role for CD5-CK2 pathway in T cell activation and persistence of effector T cells in neuroinflammatory disease. This study predicts that targeting of IFN-⁺/IL-17⁺ infiltrating Th cells will be useful for the treatment of multiple sclerosis and other systemic autoimmune diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grants AG16221 (to C.R.), NS46032 (to S.R.B.), T32-AR07450-23 (to R.C.A.), and by the Lupus Research Institute (to C.R.).

² Address correspondence and reprint requests to Dr. Chander Raman, Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, SHEL 305, 1530 Third Avenue South, Birmingham, AL 35294-0007. E-mail address: craman{at}uab.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; T_H1, infiltrating Th cell 1; MOG, myelin oligodendrocyte glycoprotein; DiOC₆, dihexyloxacarbocyanine; AICD, activation-induced cell death; DLN, draining lymph node; T_n, naive T cell.

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