Polyfunctional T cells — having the ability to secrete cytokines and chemokines and to mediate cytolysis — are highly predictive of protective immunity but often become exhausted in chronic infections in response to persistent antigen stimulation, through a mechanism that is only partly determined by the upregulation of inhibitory receptors such as programmed cell death protein 1 (PD1). This study shows that high antigen concentration decreases the proportion of polyfunctional T cells in both memory and naive CD8+ T cell populations in a manner independent of PD1 signalling but dependent on the MAPK ERK pathway. High levels of antigen upregulate expression of sprouty 2 (SPRY2), a negative regulator of MAPK ERK signalling. HIV-specific patient T cells have increased levels of SPRY2, and SPRY2 knockdown in these T cells increased HIV-specific polyfunctionality.