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In Vivo Ligation of CD40 Enhances Priming Against the Endogenous Tumor Antigen and Promotes CD8⁺ T Cell Effector Function in SV40 T Antigen Transgenic Mice¹

Kevin Staveley-O’Carroll^*,, Todd D. Schell^*, Marcela Jimenez, Lawrence M. Mylin^2,*, M. Judith Tevethia^*, Stephen P. Schoenberger and Satvir S. Tevethia^3,*

Departments of ^* Microbiology and Immunology and Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033; and Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

The ability to initiate and sustain CD8⁺ T cell responses to tumors in vivo is hindered by the development of peripheral T cell tolerance against tumor-associated Ags. Approaches that counter the onset of T cell tolerance may preserve a pool of potentially tumor-reactive CD8⁺ T cells. Administration of agonist Ab to the CD40 molecule, expressed on APCs, can enhance immunization approaches targeting T lymphocytes in an otherwise tolerance-prone environment. In this report, the effects of anti-CD40 administration on priming of naive CD8⁺ T cells against an endogenous tumor Ag were investigated. Line 501 mice express the SV40 large T Ag oncoprotein as a transgene from the -amylase promoter, resulting in the development of peripheral CD8⁺ T cell tolerance to the H-2-D^b-restricted immunodominant epitope I of T Ag by 6 mo of age, before the appearance of osteosarcomas. We demonstrate that naive epitope I-specific TCR transgenic (TCR-I) T cells undergo peripheral tolerance following adoptive transfer into 6-mo-old 501 mice. In contrast, administration of agonistic anti-CD40 Ab led to increased expansion of TCR-I T cells in 501 mice, the acquisition of effector function by TCR-I T cells and the establishment of T cell memory. Importantly, this enhanced priming effect of anti-CD40 administration did not require immunization and was effective even if administered after naive TCR-I T cells had encountered the endogenous T Ag. Thus, anti-CD40 administration can block the onset of peripheral tolerance and enhance the recruitment of functionally competent effector T cells toward an endogenous tumor Ag.

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