T cell competition profoundly reduces the effect of initial precursor frequency on the generation of CD4 T cell memory

Abstract

Protective immune responses are accompanied by increases in the frequency of high affinity T cells, which contribute to subsequent immunological memory. There is evidence that the fold-change in T cell number during the immune response is inversely related to initial precursor frequency, but the size of this effect remains poorly defined. Indeed, in many reports precursor frequency has been considered as directly proportional to the magnitude of the response. We have determined the effect of initial precursor frequency over the course of an in vivo antigen-specific response, in an experimental setting in which the other variables, TCR affinity and antigen dose, are kept constant. A major effect of precursor frequency was apparent in both the expansion and contraction phases; low initial precursor frequency in the physiological range was associated with greater initial expansion in T cell numbers, and also with preferential retention of memory cells. The effect was seen continuously across a 1000-fold naive cell frequency range, leading to memory cell frequencies that differed by only 3-fold. These results are consistent with the existence of ongoing competition for antigen throughout the course of the immune response and explain the paradoxical ability of populations of genetically diverse individuals to make appropriate protective immune responses despite the large differences in initial repertoire that result from semi-random thymic TCR repertoire generation and selection.