IL7Rα Contributes to Experimental Autoimmune Encephalomyelitis through Altered T Cell Responses and Nonhematopoietic Cell Lineages

A mutation in the IL7R alpha locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Ra has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. In this study, we use the experimental autoimmune encephalomyelitis (EAE) model of MS to show that a less severe form of the disease results when IL7R alpha expression is largely restricted to thymic tissue in IL7RTg(IL7R-/-) mice. Compared with wild-type (WT) mice, IL7RTg(IL7R-/-) mice exhibited reduced paralysis and myelin damage that correlated with dampened effector responses, namely decreased TNF production. Furthermore, treatment of diseased WT mice with neutralizing anti-IL7R alpha Ab also resulted in significant improvement of EAE. In addition, chimeric mice were generated by bone marrow transplant to limit expression of IL7R alpha to cells of either hematopoietic or nonhematopoietic origin. Mice lacking IL7R alpha only on hematopoietic cells develop severe EAE, suggesting that IL7R alpha expression in the nonhematopoietic compartment contributes to disease. Moreover, novel IL7R alpha expression was identified on astrocytes and oligodendrocytes endogenous to the CNS. Chimeric mice that lack IL7R alpha only on nonhematopoietic cells also develop severe EAE, which further supports the role of IL7R alpha in T cell effector function. Conversely, mice that lack IL7R alpha throughout both compartments are dramatically protected from disease. Taken together, these data indicate that multiple cell types use IL7R alpha signaling in the development of EAE, and inhibition of this pathway should be considered as a new therapeutic avenue for MS. The Journal of Immunology, 2013, 190:4525-4534.