Published online before print June 26, 2008

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2008.080142v1 173/2/411    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Elyaman, W. Articles by Khoury, S. J. PubMed PubMed Citation Articles by Elyaman, W. Articles by Khoury, S. J.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.080142

Accepted for publication May 13, 2008.

Article

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, Mohamed H. Sayegh, and Samia J. Khoury^*@

*Center for Neurologic Diseases, Brigham and Women's Hospital, and Transplantation Center, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: skhoury{at}rics.bwh.harvard.edu.

	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- and less interleukin-17 compared to effector T cells. Moreover, adoptive transfer of memory T cells into T cell receptor (TCR)^-/- 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.