Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery (159.7)

Abstract

Abstract It is currently not understood how some chronic infections exhaust antigen-specific T cells over time and how different pathogen components contribute to the exhausted state. 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 persistent inflammation and disease progression. In this system presentation of an MHC-II presented antigen is restricted to dendritic cells so that confounding B, CD8+ T, or innate cell responses are not triggered. 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 with 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 at a high dose rapidly induces a dysfunctional state in CD4+ T cells that is only partially reversible upon antigen removal. At a low dose, however, antigen has to persist longer before T cell impairment becomes detectable.