Negative selection of T cells occurs throughout thymic development

Thymic positive and negative selections govern the development of a self-MH C-reactive, yet self-tolerant, T cell repertoire. Whether these processes o ccur independently or sequentially remains controversial. To investigate th ese issues, we have employed tetrameric peptide-MHC complexes to fluorescen tly label and monitor polyclonal populations of thymocytes that are specifi c for moth cytochrome c (MCC)/I-E-k. In TCR beta mice tetramer-positive thy mocytes are detectable even in the most immature TCR-expressing cells. Zn t he presence of MCC peptide, thymocytes that bind strongly to MCC/I-E-k tetr amers are deleted earlier in development and more extensively than cells th at bind weakly, This negative selection of the MCC/I-E-k-specific cells occ urs continuously throughout development and before any evidence of positive selection. Thus, positive and negative selections are independent processe s that need not occur sequentially.