IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-β in multiple sclerosis

• Published in: Science translational medicine 2011-07, Vol.3 (93), p.93ra68-93ra68
• Main Authors: Lee, Li-Fen, Axtell, Robert, Tu, Guang Huan, Logronio, Kathryn, Dilley, Jeanette, Yu, Jessica, Rickert, Mathias, Han, Bora, Evering, Winston, Walker, Michael G, Shi, Jing, de Jong, Brigit A, Killestein, Joep, Polman, Chris H, Steinman, Lawrence, Lin, John C
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; Antibody Specificity - drug effects; Cell Differentiation - drug effects; Encephalomyelitis, Autoimmune, Experimental - blood; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Humans; Immunologic Memory - drug effects; Interferon-beta - immunology; Interferon-beta - therapeutic use; Interleukin-7 - blood; Interleukin-7 - immunology; Mice; Multiple Sclerosis - blood; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Receptors, Interleukin-7 - antagonists & inhibitors; Th1 Cells - cytology; Th1 Cells - drug effects; Th1 Cells - immunology; Treatment Outcome
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.3002400

The interleukin-7 receptor α chain (IL-7Rα) gene was identified as a top non-major histocompatibility complex-linked risk locus for multiple sclerosis (MS). Recently, we showed that a T helper 1 (T(H)1)-driven, but not a T(H)17-driven, form of MS exhibited a good clinical response to interferon-β (IFN-β) therapy. We now demonstrate that high serum levels of IL-7, particularly when paired with low levels of IL-17F, predict responsiveness to IFN-β and hence a T(H)1-driven subtype of MS. We also show that although IL-7 signaling is neither necessary nor sufficient for the induction or expansion of T(H)17 cells, IL-7 can greatly enhance both human and mouse T(H)1 cell differentiation. IL-7 alone is sufficient to induce human T(H)1 differentiation in the absence of IL-12 or other cytokines. Furthermore, targeting IL-7/IL-7Rα is beneficial in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Mice treated with IL-7Rα-blocking antibodies before or after onset of paralysis exhibited reduced clinical signs of EAE, with reduction in peripheral naïve and activated T cells, whereas central memory T, regulatory T, B, and natural killer cell populations were largely spared. IL-7Rα antibody treatment markedly reduced lymphocyte infiltration into the central nervous system in mice with EAE. Thus, a serum profile of high IL-7 may signify a T(H)1-driven form of MS and may predict outcome in MS patients undergoing IFN-β therapy. Blockade of IL-7 and the IL-7Rα pathway may have therapeutic potential in MS and other autoimmune diseases.