CD28-independent induction of experimental autoimmune encephalomyelitis

T Chitnis

N Najafian

K Abdallah

V Dong

H Yagita

M Sayegh

S Khoury

^{Center for Neurologic Diseases, and}^{Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA}^{Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan}

Address correspondence to: Samia J. Khoury, 77 Avenue Louis Pasteur, Room 714, Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. Phone: (617) 525-5370; Fax: (617) 525-5305; E-mail: ude.dravrah.hwb.scir@yruohks.

Received 2000 Sep 1; Accepted 2001 Jan 15.

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated disease initiated by antigen-specific CD4^{T cells. Signaling through CD28 is a critical second signal for activation of T cells, and CD28 knockout (CD28KO) mice have been reported to be resistant to induction of EAE. We now report that CD28KO mice have no intrinsic defect in mediating disease, because they developed EAE after passive transfer of primed T cells. After immunization, peripheral T cells from CD28KO mice were primed and developed memory phenotype, but had decreased antigen-specific IFN-γ production as compared with cells from wild-type (WT) animals. Reimmunization of CD28KO mice brought out clinical disease and increased IFN-γ production in vitro. Pathologically, there were cellular infiltrates in the central nervous system, in contrast to single-immunized mice. We show furthermore that blocking B7-1 or CTLA4, but not B7-2, in CD28KO mice induces disease after a single immunization. Thus, EAE can be induced in animals lacking CD28-dependent costimulation, suggesting that alternative costimulatory pathways were used. Blocking the OX40-OX40L costimulatory pathway differentially affected disease induction in CD28KO mice as compared with WT controls. Our data show that EAE may develop in the absence of CD28 T-cell costimulation. These findings have implications for therapies aimed at blocking costimulatory signals in autoimmune diseases.}

Abstract

Acknowledgments

This work is supported by research grants from the National Multiple Sclerosis Society (RG-2589 to S.J. Khoury and FG-1287 to T. Chitnis) and the NIH (AI-40945 to S.J. Khoury and PO1 AI-41521 to M.H. Sayegh). N. Najafian is a fellow of the National Kidney Foundation.

Acknowledgments

Footnotes

Tanuja Chitnis and Nader Najafian contributed equally to this work.

Footnotes

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