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High Affinity Xenoreactive TCR:MHC Interaction Recruits CD8 in Absence of Binding to MHC¹

Jennifer Buslepp^*, Samantha E. Kerry, Doug Loftus, Jeffrey A. Frelinger^,, Ettore Appella and Edward J. Collins^2,*,,

Departments of ^* Biochemistry and Biophysics and Microbiology and Immunology, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599; and Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

The TCR from a xenoreactive murine cytotoxic T lymphocyte clone, AHIII 12.2, recognizes murine H-2D^b complexed with peptide p1058 (FAPGFFPYL) as well as human HLA-A2.1 complexed with human self-peptide p1049 (ALWGFFPVL). To understand more about T cell biology and cross-reactivity, the ectodomains of the AHIII 12.2 TCR have been produced in E. coli as inclusion bodies and the protein folded to its native conformation. Flow cytometric and surface plasmon resonance analyses indicate that human p1049/A2 has a significantly greater affinity for the murine AHIII 12.2 TCR than does murine p1058/D^b. Yet, T cell binding and cytolytic activity are independent of CD8 when stimulated with human p1049/A2 as demonstrated with anti-CD8 Abs that block CD8 association with MHC. Even in the absence of direct CD8 binding, stimulation of AHIII 12.2 T cells with "CD8-independent" p1049/A2 produces p56^lck activation and calcium flux. Confocal fluorescence microscopy and fluorescence resonance energy transfer flow cytometry demonstrate CD8 is recruited to the site of TCR:peptide MHC binding. Taken together, these results indicate that there exists another mechanism for recruitment of CD8 during high affinity TCR:peptide MHC engagement.

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