Evidence for a differential avidity model of T cell selection in the thymus.

Positive and negative selection of a lymphocytic choriomeningitis virus (LCMV) peptide-specific, H-2Db-restricted T cell clone (P14) was studied using TAP1- and TAP1+ mice transgenic for P14 T cell receptor (TCR) alpha and beta genes. Positive selection of transgenic CD8+ P14 cells was impaired in TAP1- mice. Addition of the LCMV peptide to TAP1- fetal thymic organ cultures (FTOCs) at low and high concentrations induced positive and negative selection of CD8+ P14 cells, respectively, while addition of the same peptide to TAP1+ FTOCs induced negative selection even at low concentrations. Both types of selection were peptide specific. Thus, a critical parameter that controls the fate of a thymocyte seems to be the number of TCRs engaged with complexes of peptide and major histocompatibility complex. When this number is low, positive selection occurs, and when it is high, negative selection takes place. These findings support a differential avidity model of T cell selection.