The paradox of alloreactivity and self MHC restriction: Quantitative analysis and statistics

Although 1-24% of T cells are alloreactive. i.e.. respond to MHC molecules encoded by a foreign haplotype, it is generally believed that T cells canno t recognize foreign peptides binding foreign MHC molecules. We show using a quantitative model that, if T cell selection and activation are affinity-d riven, then an alloreactivity of 1-24% is incompatible with the textbook no tion that self MHC restriction is absolute. If an average of 1% of clones a re alloreactive, then according to our model, at most 20-fold more clones s hould, on average, be activated by antigens presented on self MHC than by a ntigens presented on foreign MHC. This ratio is at best 5 if alloreactivity is 5%. These results describe average properties of the murine immune syst em, but not the outcome of individual experiments. Using supercomputer tech nology, we simulated 100,000 MHC restriction experiments. Although the aver age restriction ratio was 7.1. restriction was absolute in 10% of the simul ated experiments, greater than 100. although not absolute, in 29%, and belo w 6 in 24%. This extreme variability agrees with experimental estimates. Ou r analysis suggests that alloreactivity and average self MHC restriction bo th cannot be high, but that a low average restriction level is compatible w ith high levels in a significant number of experiments.