Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery

It is currently not understood how some chronic infections exhaust antigen-specific T cells over time and which pathogen components contribute to exhaustion. Here, we dissected the behavior of primed CD4(+) T cells exposed to persistent antigen using an inducible transgenic mouse system that allowed us to control antigen presentation as the only experimental variable, independent of the persistent inflammation and disease progression that complicate infectious models. Moreover, this system restricted antigen presentation to dendritic cells (DCs) and avoided confounding B, CD8(+) T, or innate cell responses. When antigen presentation was extended beyond the expansion phase, primed CD4(+) T cells survived, but exhibited reduced memory functionality in terms of their proliferative capacity and cytokine expression potential. The effect was antigen dose and time dependent, not associated with increased PD-1 expression or reduced calcium influx, but impaired Jun phosphorylation in response to TCR engagement. Upon antigen removal, the cells regained the ability to proliferate, but remained unable to produce high levels of IL-2 and TNF-α. These data show that persistent antigen by itself rapidly induces a dysfunctional state in CD4(+) T cells that is only partially reversible upon antigen removal. These findings have implications for vaccine optimization and for the possible reinvigoration of CD4(+) T cells during chronic infection.