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Original Article

George S. Vratsanos^a, Sungsoo Jung^a, Yeong-Min Park^a, and Joe Craft^a

^a Section of Rheumatology, Department of Medicine, and the Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520
Box 208031, 610 LCI, 333 Cedar Street, New Haven, CT 06520-8031.203-785-7053203-785-7063

joseph.craft{at}yale.edu

Polyclonal CD4⁺ T cell activation is characteristic of spontaneous lupus. As a potential explanation for this phenotype, we hypothesized that T cells from lupus-prone mice are intrinsically hyperresponsive to stimulation with antigen, particularly to those peptide ligands having a low affinity for the T cell receptor (TCR). To test this hypothesis, we backcrossed the and β chain genes of the AND TCR specific for amino acids 88–104 of pigeon cytochrome C (PCC) to the Fas-intact MRL/Mp^+Fas-lpr and to the H-2^k–matched control backgrounds B10.BR and CBA/CaJ (MRL.AND, B10.AND, and CBA.AND, respectively), and assessed naive CD4⁺ TCR transgenic T cell activation in vitro after its encounter with cognate antigen and lower affinity altered peptide ligands (APLs). MRL.AND T cells, compared with control B10.AND and CBA.AND cells, proliferated more when stimulated with agonist antigen. More strikingly, MRL.AND T cells proliferated significantly more and produced more interleukin 2 when stimulated with the APLs of PCC 88–104, having lower affinity for the transgenic TCR. These results imply that one of the forces driving polyclonal activation of /β T cells in lupus is an intrinsically heightened response to peptide antigen, particularly those with low affinity for the TCR, independent of the nature of the antigen-presenting cell and degree of costimulation.

Key Words: autoreactive T cells • autoimmunity • systemic lupus erythematosus • tolerance • murine lupus

G.S. Vratsanos and S. Jung contributed equally to this work.

S. Jung's present address is Dept. of Internal Medicine, The Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul 133-792, South Korea. Y. Park's present address is Dept. of Microbiology and Immunology, Pusan National University College of Medicine, Pusan 602-739, South Korea.

© 2001 The Rockefeller University Press

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