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Activation of Naive CD4⁺ T Cells In Vivo by a Self-Peptide Mimic: Mechanism of Tolerance Maintenance and Preservation of Immunity¹

Jin-Young Choi^* and Joe Craft^2,*,

Sections of ^* Rheumatology and Immunobiology, Yale School of Medicine, New Haven, CT 06520

Intrathymic selection generates a peripheral repertoire of CD4⁺ T cells with receptors that retain low affinity for self-peptide MHC complexes. Despite self-recognition, T cells remain tolerant even in the setting of microbial challenge and resultant costimulatory signals. We demonstrate here a novel mechanism for tolerance maintenance under conditions of self-recognition and strong costimulation. TCR engagement in vivo with a low-avidity peptide, as a mimic of self, provided with poly(I:C) (dsRNA) led to division of naive T cells that was dependent upon costimulatory signals; however, the dividing cells rapidly underwent deletion. By contrast, the surviving cells that were activated as evidenced by up-regulation of CD69 did not become effectors upon restimulation with the same ligand and maintained an effective response against agonist peptide. We suggest TCR engagement with self-peptide MHC complexes promotes tolerance maintenance during pathogen challenge, while preserving efficient reactivity for subsequent encounter with foreign Ags.

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