IL7R? contributes to experimental autoimmune encephalomyelitis through altered T cell responses and nonhematopoietic cell lineages.

ABSTRACT: A mutation in the IL7R? locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7R? 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? 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? Ab also resulted in significant improvement of EAE. In addition, chimeric mice were generated by bone marrow transplant to limit expression of IL7R? to cells of either hematopoietic or nonhematopoietic origin. Mice lacking IL7R? only on hematopoietic cells develop severe EAE, suggesting that IL7R? expression in the nonhematopoietic compartment contributes to disease. Moreover, novel IL7R? expression was identified on astrocytes and oligodendrocytes endogenous to the CNS. Chimeric mice that lack IL7R? only on nonhematopoietic cells also develop severe EAE, which further supports the role of IL7R? in T cell effector function. Conversely, mice that lack IL7R? throughout both compartments are dramatically protected from disease. Taken together, these data indicate that multiple cell types use IL7R? signaling in the development of EAE, and inhibition of this pathway should be considered as a new therapeutic avenue for MS.

SUBMITTER: Ashbaugh JJ 

PROVIDER: S-EPMC4120889 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature