Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection

Interactions between alpha beta T cell receptors and peptides bound to mole cules encoded by the MHC genes underly T cell activation. More than 1% of T cells are activated by foreign (allogenic) MHC molecules, a phenomenon cal led alloreactivity. Reconciling the high frequency of alloreactivity with t he fact that only 1 T cell in 10(4)-10(6) responds to a given foreign antig en presented on self MHC has been a longstanding puzzle. We show, by using a quantitative model, that this difference follows from the affinity model of T cell selection. Further, we demonstrate that highly alloreactive pre- and post-selection repertoires can be obtained without assuming germline bi as of T cell receptors toward recognition of allele-specific MHC residues. It has been proposed that alloreactivity occurs because self and foreign MH Cs bind different subsets of self peptides or alter their conformation diff erently. We find that such effects decrease rather than increase alloreacti vity. Overall, our results show that the affinity model of T cell selection can quantitatively explain both self MHC restriction and high alloreactivi ty.