Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 42, Issue 9, Pages 2354-2362Publisher
WILEY
DOI: 10.1002/eji.201242520
Keywords
Allelic exclusion; Arthritis; Autoimmunity; Dual TCR
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Funding
- University of Minnesota Department of Pediatrics
- Minnesota Medical Foundation
- U.S. National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases
- NIH [5T32AI007313]
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Allelic exclusion of antigen receptor loci is a fundamental mechanism of immunological self-tolerance. Incomplete allelic exclusion leads to dual T-cell receptor (TCR) expression and can allow developing autoreactive a beta T lymphocytes to escape clonal deletion. Because allelic exclusion at the TCR-beta locus is more stringent than at the TCR-a locus, dual TCR-beta expression has not been considered a likely contributor to autoimmunity. We show here that incomplete TCR-beta allelic exclusion permits developing thymocytes bearing the autoreactive, transgene-encoded KRN TCR to be positively selected more efficiently, thereby accelerating the onset of spontaneous autoimmune arthritis. Our findings highlight dual TCR-beta expression as a mechanism that can enhance the maturation of autoreactive pathogenic T cells and lead to more rapid development of autoimmune disease.
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