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Naive CD4⁺ T Cells from Lupus-Prone Fas-Intact MRL Mice Display TCR-Mediated Hyperproliferation Due to Intrinsic Threshold Defects in Activation¹

Christina E. Zielinski^2,*, Simon N. Jacob^3,, Farida Bouzahzah^4,*, Barbara E. Ehrlich and Joe Craft^5,*,

^* Section of Rheumatology, Department of Medicine, Departments of Pharmacology, and Cellular and Molecular Physiology, and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520

Autoreactive T cell activation is a consistent feature of murine lupus; however, the mechanism of such activation remains unclear. We hypothesized that naive CD4⁺ T cells in lupus have a lower threshold of activation through their TCR-CD3 complex that renders them more susceptible to stimulation with self-Ags. To test this hypothesis, we compared proliferation, IL-2 production, and single cell calcium signaling of naive CD4⁺ T cells isolated from Fas-intact MRL/+^Fas-lpr mice with H-2^k-matched B10.BR and CBA/CaJ controls, following anti-CD3 stimulation in the presence or absence of anti-CD28. We also assessed the responsiveness of naive CD4⁺ T cells isolated from Fas-intact MRL and control mice bearing a rearranged TCR specific for amino acids 88–104 of pigeon cytochrome c to cognate and low affinity peptide Ags presented by bone marrow-matured dendritic cells. TCR transgenic and wild-type CD4⁺ T cells from MRL mice displayed a lower threshold of activation than control cells, a response that was class II MHC dependent. The rise in intracellular calcium in MRL vs controls was enhanced and prolonged following anti-CD3 triggering, suggestive of proximal defects in TCR-engendered signaling as the mechanism for the observed hyperactivity. These findings were observed as early as 1–2 mo postweaning and, based on analysis of F₁ T cells, appeared to be dominantly expressed. This genetically altered threshold for activation of MRL T cells, a consequence of a proximal defect in CD3-mediated signal transduction, may contribute to the abrogation of T cell tolerance to self-Ags in lupus.

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