Limits to the differential avidity model of T cell selection in the thymus

It has been postulated that the critical feature that determines the developmental fate of an immature thymocyte is the avidity of interaction between thymocyte TCR and peptide/MHC molecules on thymic stromal cells. However, it is possible that certain innate properties of peptides predispose them to triggering only positive or negative selection irrespective of their density on thymic stromal cells. To distinguish between these hypotheses, we examined the ability of several different peptides to induce the positive and negative selection of TCR transgenic (P14) antilymphocytic choriomeningitis virus (LCMV) CTLs in fetal thymus organ cultures (FTOC) from TAP1+ and TAP1- mice. We found that only relatively weak agonist peptides could induce the positive selection of anti-LCMV CTLs. A nonagonist peptide could induce positive selection but not negative selection; however, a weak agonist peptide could induce the positive selection of anti-LCMV CTLs in P14 TAP1- FTOC and negative selection in P14 TAP1+ FTOC. These data imply that there are upper and lower limits for the affinity of a peptide in triggering positive or negative selection, but that for peptides of intermediate affinity the overall avidity of interaction with the P14 TCR is the critical parameter in determining the developmental fate of thymocytes. Our observations also suggest a prominent role for low affinity self peptides in selecting a function repertoire of CD8+ T cells.