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The Surprising Kinetics of the T Cell Response to Live Antigenic Cells¹

Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

Cooperation between CD4⁺ and CD8⁺ T cells is required for the proper development of primary effector and memory CD8⁺ T cells following immunization with noninflammatory immunogens. In this study, we characterized murine CD4⁺ and CD8⁺ T cell responses to male-specific minor histocompatibility (HY) Ags following injection of live male cells into females of the same strain. Male cells are rejected 10–12 days after transfer, coinciding with the expansion and effector function of CD8⁺ CTLs to two H-2D^b-restricted epitopes. Although anti-HY CD4⁺ T cell responses are readily detectable day 5 posttransfer, CD8⁺ responses are undetectable until day 10. The early CD4⁺ response is not dependent on direct presentation of Ag by donor male cells, but depends on presentation of the male cells by recipient APC. The CD4⁺ T cell response is required for the priming of CD8⁺ T cell effector responses and rejection of HY-incompatible cells. Unexpectedly, HY-specific CD4⁺ T cells are also capable of efficiently lysing target cells in vivo. The delay in the CD8⁺ T cell response can be largely abrogated by depleting T cells from the male inoculum, and donor male CD8⁺ T cells in particular suppress host anti-HY CD8⁺ responses. These data demonstrate dramatic differences in host T cell responses to noninflammatory Ags compared with responses to pathogens. We explain the delayed CD8⁺ response by proposing that there is a balance between cross-presentation of Ag by helper cell-licensed dendritic cells, on the one hand, and veto suppression by live male lymphocytes on the other.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Howard Hughes Medical Institute and National Institute of Health Grant AI19335 (to M.J.B.) and by Ruth L. Kirschstein National Research Service Award CA009537 (to A.J.T.).

² Address correspondence and reprint requests to Dr. Michael J. Bevan, Howard Hughes Medical Institute, Department of Immunology, Box 357370, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195. E-mail address: mbevan{at}u.washington.edu

³ Abbreviations used in this paper: DC, dendritic cell; LLO, listeriolysin O; ICS, intracellular cytokine staining.

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