A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Rα has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. Here we use the experimental autoimmune encephalomyelitis (EAE) model of MS to show that a less severe form of the disease results when IL7Rα expression is largely restricted to thymic tissue in IL7RTgIL7R−/− mice. Compared to wild type (WT) mice, IL7RTgIL7R−/− 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-IL7Rα antibody also resulted in significant improvement of EAE. Additionally, chimeric mice were generated by bone marrow transplant to limit expression of IL7Rα to cells of either hematopoietic or non-hematopoietic origin. Mice lacking IL7Rα only on hematopoietic cells develop severe EAE, suggesting that IL7Rα expression in the non-hematopoietic compartment contributes to disease. Moreover, novel IL7Rα expression was identified on astrocytes and oligodendrocytes endogenous to the central nervous system. Chimeric mice that lack IL7Rα only on non-hematopoietic cells also develop severe EAE, which further supports the role of IL7Rα in T cell effector function. Conversely, mice that lack IL7Rα throughout both compartments are dramatically protected from disease. Taken together, these data indicate that multiple cell types utilize IL7Rα signaling in the development of EAE, and inhibition of this pathway should be considered as a new therapeutic avenue for MS.

Summary We previously identified a population of residual Treg cells following autologous hematopoietic stem transplantation (HSCT) which rapidly undergoes significant expansion in lymphopenic transplant recipients prior to repopulation by donor de novo derived Treg cells. These CD4+Foxp3+ T cells provide protection from the development of autoimmune disease. Although ablative conditioning results in excess IL-7 and IL-15, IL-2 is typically not found at high levels following autologous HSCT. We therefore examined the role of these STAT-5 signaling cytokines in the expansion of residual Treg cells after autologous HSCT. The present studies found that residual Treg cells include surviving peripheral host Foxp3+ CD4+ T cells whose expansion was critically dependent on IL-2 which could be solely provided by surviving host cells. IL-7 was found to contribute to Treg cell homeostasis, however, not as a growth factor but rather in their persistence. In conjunction with this expansion, TCR spectratype analyses revealed that the residual host Treg cell compartment differed from that present in non-conditioned healthy mice exhibiting a limited TCR diversity. Collectively, these data indicate that the proliferation of Treg and T effector (Teff) cells post-HSCT utilize separate pools of cytokines which has important implications regarding development of clinical strategies to elicit desired immune responses in patients post-transplant.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation, demyelination, and axonal damage. Recently, a mutation in the interleukin-7 receptor alpha (IL7Rα) locus has been identified as a risk factor for MS. IL7Rα has well-documented roles in lymphocyte development, function, and homeostasis, but its involvement in disease settings is largely understudied. Here we show that IL7Rα defective mice (IL7RTgIL7R-/-) display a less severe form of experimental autoimmune encephalomyelitis (EAE), a model for MS. Compared to wild type (WT), IL7RTgIL7R-/- exhibit reduced levels of paralysis, myelin damage, and inflammation. Furthermore, diseased WT treated with neutralizing anti-IL7Rα show significant recovery in EAE clinical scores and reduced lymphocyte infiltration into the CNS. A series of chimeric mice were then generated by bone marrow (BM) transplantation to identify IL7Rα+ cellular compartments contributing to EAE. Rag-/- mice engrafted with IL7RTgIL7R-/- or WT BM display equivalent disease severity, suggesting that IL7Rα on non-hematopoietic cells contributes to EAE. Lymphodeplete IL7R-/- mice reconstituted with WT or IL7RTgIL7R-/- BM showed dramatic reductions in EAE only with IL7RTgIL7R-/- engraftment and not WT, suggesting that IL7Rα signaling on lymphocytes contributes to disease. Taken together, IL7Rα signaling blockade in multiple cell types is necessary for marked reductions in EAE, and should be considered as a new therapeutic target for MS.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by extensive inflammation, demyelination, and axonal damage. The interleukin-7 receptor alpha (IL7Rα) chain is an essential subunit for the signaling receptors of both interleukin-7 (IL7) and thymic stromal lymphopoietin (TSLP), which are involved in lymphocyte development, function, and homeostasis. Recently a mutation in the IL7Rα chain locus has been identified as a risk factor for MS. We show that mice with IL7Rα expression limited to thymic tissue (IL7RTgIL7R-/-) display a less severe form of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. However, TSLPR-/- mice showed no protection from disease. Furthermore, anti-IL7Rα treatment in wild type (WT) mice after disease onset significantly decreased EAE severity and lymphocyte infiltration into the CNS, which was accompanied by a relative increase in resident microglia. Additionally, Rag-/- chimeric mice grafted with IL7RTgIL7R-/- or WT bone marrow cells displayed equivalent disease severity, implying that IL7Rα on a non-hematopoietic cell population contributes to EAE. Taken together, our data shows that systemic blockade of IL7Rα reduces EAE severity, and therefore serves as an optimal target for MS therapies.