CD28-independent induction of experimental autoimmune encephalomyelitis
Tanuja Chitnis, … , Mohamed H. Sayegh, Samia J. Khoury
Tanuja Chitnis, … , Mohamed H. Sayegh, Samia J. Khoury
Published March 1, 2001
Citation Information: J Clin Invest. 2001;107(5):575-583. https://doi.org/10.1172/JCI11220.
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Article

CD28-independent induction of experimental autoimmune encephalomyelitis

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.

Authors

Tanuja Chitnis, Nader Najafian, Kald A. Abdallah, Victor Dong, Hideo Yagita, Mohamed H. Sayegh, Samia J. Khoury

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Anti-OX40L reverses EAE induced in double-immunized CD28KO mice but not ...
Anti-OX40L reverses EAE induced in double-immunized CD28KO mice but not in WT mice. Disease course of double-immunized CD28KO mice treated with anti-OX40L (a) or anti-CD40L (b). Mice were immunized with MOG p35-55 and graded for disease daily. The mean daily grade for each group (n = 3–10 mice per group) is shown. (a) A representative experiment showing the disease course in C57BL/6 WT mice (filled squares) or in WT mice treated with anti-OX40L Ab (filled triangles) compared with double-immunized CD28KO mice (open squares) and double-immunized CD28KO mice treated with anti-OX40L Ab (open triangles). The mean maximal disease grade in WT mice was 2.7 ± 0.1; in WT treated with anti-OX40L Ab it was 2.75 ± 0.3. The mean maximal grade in double-immunized CD28KO mice was 2.35 ± 0.3, and in those treated with anti-OX40L Ab it was 0.83 ± 0.6 (P = 0.001 compared with untreated double-immunized CD28KO). (b) A representative experiment showing the disease course in C57BL/6 WT mice (filled squares) or in WT mice treated with anti-CD40L Ab (filled triangles) compared with double-immunized CD28KO mice (open squares) and double-immunized CD28KO mice treated with anti-CD40L Ab (open triangles). The mean maximal disease grade in untreated WT mice was 2.7 ± 0.1, whereas in WT treated with anti-CD40L it was 1.08 ± 1.1 (P = 0.03). The mean maximal grade in double-immunized CD28KO mice was 2.35 ± 0.3 compared with those treated with anti-CD40L (0.67 ± 1.15; P = 0.0008 compared with untreated double-immunized CD28KO mice).