SEE PROFILE

Estimates of human ab TCR diversity suggest that there are,108 different Ag receptors in the naive T cell pool, a number that is dwarfed by the potential number of different antigenic peptide-MHC (pMHC)molecules that could be encountered. Consequently, an extremely high degree of cross-reactivity is essential for effective T cell immunity. Ag recognition by T cells is unique in that it involves a coreceptor that binds at a site distinct from the TCR to facilitate productive engagement of the pMHC. In this study, we show that the CD8 coreceptor controls T cell cross-reactivity for pMHCI Ags, thereby ensuring that the peripheral T cell repertoire is optimally poised to negotiate the competing demands of responsiveness in the face of danger and quiescence in the presence of self. The Journal of Immunology, 2010, 185: 4625–4632. C D8+ CTLs are key determinants of immunity to intra-cellular pathogens and cancer cells. CTLs recognize pro-tein Ags in the form of short peptides (8–13 aa), presented in association withMHC class I (MHCI) molecules on the surface of target cells. Almost all nucleated cells express MHCI, thereby en-abling the immune system to scan the cell surface to detect internal anomalies. The Ag specificity of CTLs is conferred by the highl