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

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 α 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 α/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.