Published 6 issues per year
ISSN Print: 1040-8401
ISSN Online: 2162-6472
Indexed in
A Nondeletional Mechanism for Central T-Cell Tolerance
ABSTRACT
To be positively selected, immature thymocytes must receive signaling through their T-cell receptor (TCR), and engagement of relatively low-affinity self-peptides permits further T-cell maturation. However, mature T cells no longer overtly respond to such low-affinity antigens, indicating that T cells acquire a higher threshold for activation during thymopoiesis. We wondered whether partial interference in positive selection could produce T cells that respond to the selecting self-peptide. This possibility was tested by injecting procainamide-hydroxylamine (PAHA), a lupus-inducing drug, into the thymus of adult normal mice. Three weeks after the second injection, IgG antichromatin antibodies appeared in the circulation and remained for several months. The murine antichromatin antibodies reacted with the (H2A-H2B)–DNA subnucleosome complex, the predominant specificity in patients with procainamide-induced lupus. In thymus organ and reaggregate cultures, PAHA had no effect on negative selection of T cells with high affinity for a co-present antigen, but acted on CD4+CD8+ immature T cells as they underwent positive selection. TCR transgenic T cells specific to cytochrome c peptide 88-104 acquired the capacity to respond to the low-affinity analogue at position 99 (lys®ala) if PAHA was present during their development. PAHA also blocked the capacity of a T-cell line to become anergic after anti-CD3 treatment, suggesting that PAHA prevents the production of negative regulators that accumulate in response to partial signaling through the TCR. These results are consistent with the view that T cells acquire self-tolerance during positive selection, and disruption of this process can result in autoreactive T cells and systemic autoimmunity.
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Germolec Dori, Kono Dwight H., Pfau Jean C., Pollard K. Michael, Animal models used to examine the role of the environment in the development of autoimmune disease: Findings from an NIEHS Expert Panel Workshop, Journal of Autoimmunity, 39, 4, 2012. Crossref
-
Fülöp Tamas, Larbi Anis, Hirokawa Katsuiku, Mocchegiani Eugenio, Lesourd Bruno, Castle Stephen, Wikby Anders, Franceschi Claudio, Pawelec Graham, Immunosupportive therapies in aging, Clinical Interventions in Aging, 2, 1, 2007. Crossref
-
Self-Tolerance, in Encyclopedic Dictionary of Genetics, Genomics and Proteomics, 2004. Crossref
-
Pollard Kenneth Michael, Autoantibodies and Autoimmunity, in Encyclopedia of Molecular Cell Biology and Molecular Medicine, 2006. Crossref
-
Cauvi D.M., Pollard K.M., Hultman P., Autoimmune Models*, in Comprehensive Toxicology, 2010. Crossref
-
Rubin Robert L, Drug-induced lupus, Expert Opinion on Drug Safety, 14, 3, 2015. Crossref
-
Pichler Werner J., Drug-induced autoimmunity, Current Opinion in Allergy and Clinical Immunology, 3, 4, 2003. Crossref
-
Reilly Timothy P., Ju Cynthia, Mechanistic perspectives on sulfonamide-induced cutaneous drug reactions, Current Opinion in Allergy and Clinical Immunology, 2, 4, 2002. Crossref
-
Zhao Yong, Rodriguez-Barbosa Jose-Ignacio, Shimizu Akira, Sachs David H., Sykes Megan, Despite efficient intrathymic negative selection of host-reactive T cells, autoimmune disease may develop in porcine thymus-grafted athymic mice: evidence for failure of regulatory mechanisms suppressing autoimmunity1, Transplantation, 75, 11, 2003. Crossref
-
Pollard K. Michael, Hultman Per, Kono Dwight H., Toxicology of Autoimmune Diseases, Chemical Research in Toxicology, 23, 3, 2010. Crossref
-
Moller David R., Chen Edward S., Genetic Basis of Remitting Sarcoidosis, American Journal of Respiratory Cell and Molecular Biology, 27, 4, 2002. Crossref