Distinct functions of autoreactive memory and effector CD4+ T cells in experimental autoimmune encephalomyelitis.
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.
Elyaman
Wassim
W
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
Kivisäkk
Pia
P
Reddy
Jay
J
Chitnis
Tanuja
T
Raddassi
Khadir
K
Imitola
Jaime
J
Bradshaw
Elizabeth
E
Kuchroo
Vijay K
VK
Yagita
Hideo
H
Sayegh
Mohamed H
MH
Khoury
Samia J
SJ
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D018960:Hyaluronan Receptors / Q000276:immunology; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D054367:Receptors, CXCR3 / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C476399:Cd44 protein, mouse; C515188:Cxcr3 protein, mouse; D018960:Hyaluronan Receptors; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054367:Receptors, CXCR3; D053262:Receptors, OX40; D007371:Interferon-gamma