Modulation of CD4 Co-Receptor Limits Spontaneous Autoimmunity When High-Affinity Transgenic TCR Specific for Self-Antigen Is Expressed on a Genetically Resistant Background

Authors

• Zsolt Illés, Harvard Medical School
• Hanspeter Waldner, Harvard Medical School
• Jay Reddy, University of Nebraska - LincolnFollow
• Ana C. Anderson, Harvard Medical SchoolFollow
• Raymond A. Sobel, Veterans Affairs Medical Center (Palo Alto, California)
• Vijay K. Kuchroo, Harvard Medical School

Document Type

Article

Date of this Version

2007

Citation

International Immunology (2007) 19(10): 1,235-1,248.

Comments

Published by Oxford University Press. US government work.

Abstract

Myelin proteolipid protein (PLP) 139–151 is an immunodominant peptide that induces experimental autoimmune encephalomyelitis (EAE) in H-2^s 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-2^s congenic B10.S background. On this resistant background, we observed a high frequency of positively selected tg CD42CD82 (DN) thymocytes and peripheral DN tg T cells. Splenic DN tg T cells responded to anti-CD3 stimulation similarly to CD41 cells, but proliferative and cytokine responses to PLP 139–151 were blunted, implying that CD4 coreceptor 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 CD41 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.