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Originally published online as doi:10.2353/ajpath.2008.080142 on June 26, 2008

Published online before print June 26, 2008
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(American Journal of Pathology. 2008;173:411-422.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080142

Distinct Functions of Autoreactive Memory and Effector CD4+ T Cells in Experimental Autoimmune Encephalomyelitis

Wassim Elyaman*, Pia Kivisäkk*, Jay Reddy*, Tanuja Chitnis*, Khadir Raddassi*, Jaime Imitola*, Elizabeth Bradshaw*, Vijay K. Kuchroo*, Hideo Yagita{ddagger}, Mohamed H. Sayegh{dagger} and Samia J. Khoury*

From the Center for Neurologic Diseases,* Brigham and Women’s Hospital, and Transplantation Center,{dagger} Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Immunology,{ddagger} Juntendo University School of Medicine, Tokyo, Japan

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){alpha}β–/– 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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