Dynamic adoption of anergy by antigen-exhausted CD4+ T cells

Exhausted immune responses to chronic diseases represent a major challenge to global health. We study CD4+ T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase and are then exposed to different levels of persistent antigen, they lose their T helper 1 (Th1) functions, upregulate exhaustion markers, resemble naturally anergic cells, and modulate their MAPK, mTORC1, and Ca2+/calcineurin signaling pathways with increasing dose and time. They also become unable to help B cells and, at the highest dose, undergo apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of T cell receptor (TCR) signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease. [Display omitted] •Th1 functionalities are reduced by persisting antigen in dose- and time-dependent manner•Signaling pathways are adjusted to persisting antigen with different sensitivities•Gene transcription is dynamically and reversibly adjusted to persisting antigen•About half of the genes affected by antigen persistence respond in a dose-specific manner In a system with regulatable antigen presentation in vivo, Trefzer et al. find TCR signaling, gene transcription, and functionalities reversibly regulated by dose and time of chronically persisting antigen. Comparisons with naturally anergic and tumor-infiltrating T cells suggest that signatures of anergy and exhaustion by antigen largely overlap.