Original Article

CD4⁺ T Cells from Lupus-prone Mice Are Hyperresponsive to T Cell Receptor Engagement with Low and High Affinity Peptide Antigens: A Model to Explain Spontaneous T Cell Activation in Lupus

Correspondence to: Joe Craft, Box 208031, 610 LCI, 333 Cedar Street, New Haven, CT 06520-8031. Tel:203-785-7063 Fax:203-785-7053 E-mail: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 ß 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 /ß 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

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