In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+ T cell inflammation.
A current paradigm states that non-antigen-specific inflammatory cues attract noncognate, bystander T cell specificities to sites of infection and autoimmune inflammation. Here we show that cues emanating from a tissue undergoing spontaneous autoimmune inflammation cannot recruit naive or activated bystander T cell specificities in the absence of local expression of cognate antigen. We monitored the recruitment of CD8(+) T cells specific for the prevalent diabetogenic epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(206-214) in gene-targeted nonobese diabetic (NOD) mice expressing a T cell "invisible" IGRP(206-214) sequence. These mice developed islet inflammation and diabetes with normal incidence and kinetics, but their inflammatory lesions could recruit neither naive (endogenous or exogenous) nor ex vivo-activated IGRP(206-214)-reactive CD8(+) T cells. Conversely, IGRP(206-214)-reactive, but not nonautoreactive CD8(+) T cells rapidly homed to and accumulated in the inflamed islets of wild-type NOD mice. Our results indicate that CD8(+) T cell recruitment to a site of autoimmune inflammation results from an active process that is strictly dependent on local display of cognate pMHC and suggest that CD8(+) T cells contained in extralymphoid autoimmune lesions are largely autoreactive.
Wang
Jinguo
J
Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases,, University of Calgary, Calgary, AB, Canada T2N 4N1.
Tsai
Sue
S
Shameli
Afshin
A
Yamanouchi
Jun
J
Alkemade
Gonnie
G
Santamaria
Pere
P
D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D005952:Glucose-6-Phosphatase / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D011506:Proteins / Q000276:immunology*
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D011506:Proteins; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse