Summary: Role of IL-7R in CNS Autoimmunity
IL-7 is an essential cytokine for the development of T and B cells and plays an important role in
inflammation by stimulating Th1, Th17 cells and GM-CSF production. The IL-7 receptor (IL-7R) complex
consists of IL-7R alpha-chain (IL-7Ra) and common ¿-chain (¿c) and polymorphisms in the IL-7Ra gene
are associated with an increased risk for the development of multiple sclerosis (MS), an inflammatory
demyelinating disease of the central nervous system (CNS). Although these observations suggest that
signaling through IL-7R has a pathogenic role in CNS autoimmunity, its underlying mechanisms are
unclear. In this regard, we have made the following preliminary observations: 1) Dendritic cells (DCs)
express IL-7Ra in homeostatic conditions and during experimental autoimmune encephalomyelitis
(EAE), an animal model of MS; 2) conditional knockout (cKO) mice lacking the IL-7Ra gene in DCs are
protected from EAE; 3) IL-7Ra cKO EAE mice have a significant increase in IL-9+Foxp3+ regulatory T
(Treg) cells; 4) IL-7Ra cKO DCs produce the vasoactive polypeptide Endothelin-1 (Edn-1); 5) DC-derived
Edn-1 induces IL-9 production by T cells; and 6) Ab-mediated depletion of Treg cells or IL-9 restores EAE
susceptibility in IL-7Ra cKO mice. Together, these and other observations form the bases of our
hypothesis that IL-7Ra in DCs enhances EAE severity by suppressing the development of Edn-1-
induced IL-9+ Treg cells. We will test this hypothesis in three Specific aims: 1) To dissect the
mechanisms by which IL-7Ra downregulates Edn-1 production by DCs and promotes EAE. We will study
the mechanisms by which IL-7Ra suppresses Edn-1 in mouse and human DCs, and the role of DC-
derived Edn-1 on neuroinflammation by genetic ablation and inducible expression. 2) To investigate the
signaling pathways by which Edn-1 induces IL-9+Foxp3+ Treg cells. We will investigate the mechanisms
of IL-9 induction in Foxp3+ Treg cells by ETBR signaling by genetic approaches in vivo and in vitro, and
study the effect of dimethyl fumarate, a common therapy for MS, on the expression profile of IL-7Ra+DCs,
IL-9+Foxp3+ Treg cells and Edn-1 and its receptors in MS patients. 3) To test the therapeutic effect of
Edn-1 and its analogues in EAE. This will be tested in myelin-reactive T cells, and multiple EAE models,
including relapsing-remitting and chronic progressive EAE.
Overall impact: Experiments in this study focusing on IL-7Ra, a genetic risk factor for MS, will
enhance our understanding of the pathways and cellular interactions that promote CNS autoimmunity as
well as investigate novel approaches to treat MS.