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Tolerant CD8 T Cells Induced by Multiple Injections of Peptide Antigen Show Impaired TCR Signaling and Altered Proliferative Responses In Vitro and In Vivo¹

Patrice M. Dubois^2,*, Maria Pihlgren^*, Martine Tomkowiak^*, Marcelle Van Mechelen and Jacqueline Marvel^*

^* Immunologie Cellulaire, Laboratoire de Biologie Moléculaire et Cellulaire, Ecole Normale Supérieure de Lyon Centre National de la Recherche Scientifique, Lyon, France; and Laboratoire de Physiologie Animale, Université Libre de Bruxelles, Brussels, Belgium

The mechanisms responsible for peripheral CD8 T cell tolerance to foreign Ags remain poorly understood. In this study we have characterized the state of CD8 T cell tolerance induced in F5 TCR transgenic mice by multiple peptide injections in vivo. The tolerant state of CD8 T cells is characterized by impaired proliferative responses, increased sensitivity to cell death, and failure to acquire cytotoxic effector function after in vitro antigenic challenge. In vivo monitoring of CD8 T cell proliferation using 5-carboxyfluorescein diacetate succinimidyl ester showed that a large subset of the tolerant T cell population failed to divide in response to peptide. TCR down-regulation could not account for this loss of responsiveness to Ag since recombination-activating gene-1 (RAG-1)^-/-F5 CD8 T cell responses were similar to those of RAG-1^-/-F5 x RAG-1^-/- F₁ T lymphocytes, which express lower levels of the transgenic TCR. Analysis of early signal transduction in tolerant CD8 T cells revealed high basal levels of cytoplasmic calcium as well as impaired calcium mobilization and tyrosine phosphorylation after cross-linking of CD3 and CD8. Together these data indicate that repeated exposure to soluble antigenic peptide in vivo can induce a state of functional tolerance characterized by defective TCR signaling, impaired proliferation, and increased sensitivity to cell death.

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