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 Ca ²⁺ /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.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)