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

Abstract

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.

• Authors: Li-Fen Lee, Robert Axtell, Guang Huan Tu, Kathryn Logronio, Jeanette Dilley, Jessica Yu, Mathias Rickert, Bora Han, Winston Evering, Michael G Walker, Jing Shi, Brigit A de Jong, Joep Killestein, Chris H Polman, Lawrence Steinman, John C Lin
• Journal: Science translational medicine (Sci Transl Med) Vol. 3 Issue 93 Pg. 93ra68 (Jul 27 2011) ISSN: 1946-6242 [Electronic] United States
• PMID: 21795588 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Interleukin-7
• Receptors, Interleukin-7
• interleukin-7 receptor, alpha chain
• Interferon-beta

Topics

• Animals
• Antibodies (pharmacology)
• Antibody Specificity (drug effects)
• Cell Differentiation (drug effects)
• Encephalomyelitis, Autoimmune, Experimental (blood, drug therapy, immunology, pathology)
• Humans
• Immunologic Memory (drug effects)
• Interferon-beta (immunology, therapeutic use)
• Interleukin-7 (blood, immunology)
• Mice
• Multiple Sclerosis (blood, drug therapy, immunology, pathology)
• Receptors, Interleukin-7 (antagonists & inhibitors)
• Th1 Cells (cytology, drug effects, immunology)
• Treatment Outcome