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Negative Selection of T Cells Occurs Throughout Thymic Development¹

Kristin K. Baldwin^2,*, Brian P. Trenchak^,, John D. Altman^§ and Mark M. Davis3^,

^* Program in Immunology, Department of Microbiology and Immunology, and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305; and ^§ Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322

Thymic positive and negative selections govern the development of a self-MHC-reactive, yet self-tolerant, T cell repertoire. Whether these processes occur independently or sequentially remains controversial. To investigate these issues, we have employed tetrameric peptide-MHC complexes to fluorescently label and monitor polyclonal populations of thymocytes that are specific for moth cytochrome c (MCC)/I-E^k. In TCR ß mice tetramer-positive thymocytes are detectable even in the most immature TCR-expressing cells. In the presence of MCC peptide, thymocytes that bind strongly to MCC/I-E^k tetramers are deleted earlier in development and more extensively than cells that bind weakly. This negative selection of the MCC/I-E^k-specific cells occurs continuously throughout development and before any evidence of positive selection. Thus, positive and negative selections are independent processes that need not occur sequentially.

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