Editing autoreactive TCR enables efficient positive selection.
Allelic exclusion is inefficient at the TCRalpha locus, allowing a sizeable portion of T cells to carry two functional TCRs. The potential danger of dual TCR expression is a rescue of autoreactive TCRs during selection in the thymus and subsequent development of autoimmunity. In this study, we examine the reason(s) for replacing an autoreactive TCR and for allowing the survival of cells carrying two TCRs. We compared development of TCR transgenic CD4(+)CD8(-) thymocytes in the presence or absence of MHC class II autoantigen that does not induce deletion of thymocytes. Contrary to the expected negative effect of the presence of autoantigen, approximately 100% more CD4(+)CD8(-) thymocytes were found in the presence of MHC class II autoantigen than in the neutral background. A further increase in the strength of autoantigenic signal via expression of a human CD4 transgene led to an additional increase in the numbers of CD4(+)CD8(-) thymocytes. Thus, editing autoreactive TCR results in more efficient positive selection, and this may be both a reason and a reward for risking autoimmunity.
Santori
Fabio R
FR
Michael Heidelberger Division of Immunology, Department of Pathology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
Arsov
Ivica
I
Lilić
Mirjana
M
Vukmanović
Stanislav
S
Lili
Mirjana
M
D000483:Alleles; D000818:Animals; D001324:Autoantigens; D015551:Autoimmunity / Q000235:genetics*; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015536:Down-Regulation; D015329:Gene Rearrangement, T-Lymphocyte; D019672:Genes, T-Cell Receptor; D006183:H-2 Antigens / Q000235:genetics; D006182:H-Y Antigen / Q000235:genetics; D000949:Histocompatibility Antigens Class II; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017393:RNA Editing
D001324:Autoantigens; D015704:CD4 Antigens; D006183:H-2 Antigens; C108513:H-2A antigen; D006182:H-Y Antigen; D000949:Histocompatibility Antigens Class II