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International Immunology Advance Access originally published online on September 5, 2007
International Immunology 2007 19(10):1235-1248; doi:10.1093/intimm/dxm094
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Modulation of CD4 co-receptor limits spontaneous autoimmunity when high-affinity transgenic TCR specific for self-antigen is expressed on a genetically resistant background

Zsolt Illés1, Hanspeter Waldner1, Jayagopala Reddy1, Ana C. Anderson1, Raymond A. Sobel2,3 and Vijay K. Kuchroo1

1 Center for Neurologic Diseases, Harvard Institute of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
2 Laboratory Service, Veterans Affairs Medical Center, Palo Alto, CA 94304, USA
3 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA

Correspondence to: Z. Illes; E-mail: zsolt.illes{at}aok.pte.hu

Myelin proteolipid protein (PLP) 139–151 is an immunodominant peptide that induces experimental autoimmune encephalomyelitis (EAE) in H-2s SJL/J mice. While PLP 139–151-specific TCR transgenic (tg) 4E3 mice develop fulminant spontaneous disease on the susceptible SJL/J background, spontaneous EAE is dramatically reduced on the H-2s congenic B10.S background. On this resistant background, we observed a high frequency of positively selected tg CD4–CD8– (DN) thymocytes and peripheral DN tg T cells. Splenic DN tg T cells responded to anti-CD3 stimulation similarly to CD4+ cells, but proliferative and cytokine responses to PLP 139–151 were blunted, implying that CD4 co-receptor down-regulation modulated T cell responses to the self-antigen in vitro. Adoptive transfer of tg DN CD3hi cells into RAG-deficient wild-type (WT) recipients induced EAE less efficiently than transfer of CD4+ T tg cells indicating the blunted responses of DN tg T cells to self-antigen in vivo. The frequency of tg DN T cells was irrespective of thymic expression of the autoantigen. These data implicate that down-regulation of CD4 co-receptor in the thymus, which is independent from the expression of thymic autoantigen, results in a blunted response to the autoantigen in the periphery and limits the incidence of spontaneous autoimmunity in genetically resistant mice bearing a large autoreactive tg T cell repertoire.

Keywords: anergy, EAE/MS, suppression, T lymphocytes, tolerance

Transmitting editor: A. Falus

Received 6 March 2007, accepted 31 July 2007.


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