Modulation of CD4 co-receptor limits spontaneous autoimmunity when high-affinity transgenic TCR specific for self-antigen is expressed on a genetically resistant background.
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 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.
Illés
Zsolt
Z
Center for Neurologic Diseases, Harvard Institute of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. zsolt.illes@aok.pte.hu
Waldner
Hanspeter
H
Reddy
Jayagopala
J
Anderson
Ana C
AC
Sobel
Raymond A
RA
Kuchroo
Vijay K
VK
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D015854:Up-Regulation