Distinct functions of autoreactive memory and effector CD4+ T cells in experimental autoimmune encephalomyelitis |
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Authors: | Elyaman Wassim Kivisäkk Pia Reddy Jay Chitnis Tanuja Raddassi Khadir Imitola Jaime Bradshaw Elizabeth Kuchroo Vijay K Yagita Hideo Sayegh Mohamed H Khoury Samia J |
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Institution: | Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA. |
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Abstract: | The persistence of human autoimmune diseases is thought to be mediated predominantly by memory T cells. We investigated the phenotype and migration of memory versus effector T cells in vivo in experimental autoimmune encephalomyelitis (EAE). We found that memory CD4(+) T cells up-regulated the activation marker CD44 as well as CXCR3 and ICOS, proliferated more and produced more interferon-gamma and less interleukin-17 compared to effector T cells. Moreover, adoptive transfer of memory T cells into T cell receptor (TCR)alphabeta(-/-) recipients induced more severe disease than did effector CD4(+) T cells with marked central nervous system inflammation and axonal damage. The uniqueness of disease mediated by memory T cells was confirmed by the differential susceptibility to immunomodulatory therapies in vivo. CD28-B7 T cell costimulatory signal blockade by CTLA4Ig suppressed effector cell-mediated EAE but had minimal effects on disease induced by memory cells. In contrast, ICOS-B7h blockade exacerbated effector T cell-induced EAE but protected from disease induced by memory T cells. However, blockade of the OX40 (CD134) costimulatory pathway ameliorated disease mediated by both memory and effector T cells. Our data extend the understanding of the pathogenicity of autoreactive memory T cells and have important implications for the development of novel therapies for human autoimmune diseases. |
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