Autoantigen recognition is required for recruitment of IGRP(206-214)-autoreactive CD8+ T cells but is dispensable for tolerance.
The progression of autoimmune responses is associated with an avidity maturation process driven by preferential expansion of high avidity clonotypes at the expense of their low avidity counterparts. Central and peripheral tolerance hinder the contribution of high-avidity clonotypes targeting residues 206-214 of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP(206-214)) during the earliest stages of autoimmune diabetes. In this study, we probe the molecular determinants and biochemical consequences of IGRP(206-214)/K(d) recognition by high-, intermediate-, and low-avidity autoreactive CD8+ T cells, and we investigate the effects of genetic IGRP(206-214) silencing on their developmental biology. We find that differences in avidity for IGRP(206-214)/K(d) map to CDR1α and are associated with quantitative differences in CD3ε proline-rich sequence exposure and Nck recruitment. Unexpectedly, we find that tolerance of high-avidity CD8+ T cells, unlike their activation and recruitment into the pancreas, is dissociated from recognition of IGRP(206-214), particularly in adult mice. This finding challenges the view that tolerance of pathogenic autoreactive T cells is invariably triggered by recognition of the peptide-MHC complex that drives their activation in the periphery, indicating the existence of mechanisms of tolerance that are capable of sensing the avidity, hence pathogenicity of autoreactive T cells without the need to rely on local autoantigen availability.
Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Jinguo
J
Wang
Sue
S
Tsai
Bingye
B
Han
Pankaj
P
Tailor
Pere
P
Santamaria
D000375:Aging / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D020868:Gene Silencing; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D001324:Autoantigens; D011506:Proteins; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse