Search

Exhausted immune responses to chronic diseases represent a major challenge to global health. We studied CD4+ T cells in a mouse model where presentation of their antigen can be regulated. When the cells are driven through the effector phase, but are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion and anergy markers, modulate their MAP kinase, mTORC1 and Ca2+/calcineurin signaling pathways with dose and time, lose their capacity to transmit help to B cells and undergo, at the highest dose, apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. The cells also adapt to antigen removal and 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.

Summary: 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.