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

Authors

• Wassim Elyaman, Brigham and Women’s Hospital, Boston, MA
• Pia Kivisäkk, Brigham and Women’s Hospital, Boston, MA
• Jay Reddy, University of Nebraska - LincolnFollow
• Tanuja Chitnis, Brigham and Women’s Hospital, Boston, MA
• Khadir Raddassi, Brigham and Women’s Hospital, Boston, MA
• Jaime Imitola, Brigham and Women’s Hospital, Boston, MA
• Elizabeth Bradshaw, Brigham and Women’s Hospital, Boston, MA
• Vijay K. Kuchroo, Brigham and Women’s Hospital, Boston, MA
• Hideo Yagita, Juntendo University School of Medicine, Tokyo
• Mohamed H. Sayegh, Brigham and Women’s Hospital, Boston, MA
• Samia J. Khoury, Brigham and Women’s Hospital, Boston, MAFollow

Document Type

Article

Date of this Version

8-2008

Citation

Published in American Journal of Pathology (August 2008) 173(2): 411-422. DOI: 10.2353/ajpath.2008.080142.

Comments

Copyright 2008, American Society for Investigative Pathology and Elsevier. Used by permission.

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