LIMITS TO THE DIFFERENTIAL AVIDITY MODEL OF T-CELL SELECTION IN THE THYMUS

It has been postulated that the critical feature that determines the d evelopmental fate of an immature thymocyte is the avidity of interacti on between thymocyte TCR and peptide/MHC molecules on thymic stromal c ells, However, it is possible that certain innate properties of peptid es predispose them to triggering only positive or negative selection i rrespective of their density on thymic stromal cells, To distinguish b etween these hypotheses, we examined the ability of several different peptides to induce the positive and negative selection of TCR transgen ic (P14) antilymphocytic choriomeningitis virus (LCMV) CTLs in fetal t hymus organ cultures (FTOC) from TAP1(+) and TAP1(-) mice, We found th at only relatively weak agonist peptides could induce the positive sel ection of anti-LCMV CTLs. A nonagonist peptide could induce positive s election but not negative selection; however, a weak agonist peptide c ould induce the positive selection of anti-LCMV CTLs in P14 TAP1(-) FT OC and negative selection in P14 TAP1(+) FTOC, These data imply that t here are upper and lower limits for the affinity of a peptide in trigg ering positive or negative selection, but that for peptides of interme diate affinity the overall avidity of interaction with the P14 TCR is the critical parameter in determining the developmental fate of thymoc ytes. Our observations also suggest a prominent role for low affinity self peptides in selecting a function repertoire of CD8(+) T cells.