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Trefzer, Anne; Kadam, Pallavi; Wang, Shu-Hung; Pennavaria, Stefanie; Lober, Benedikt; Akcabozan, Batuhan; Kranich, Jan; Brocker, Thomas; Nakano, Naoko; Irmler, Martin; Beckers, Johannes; Straub, Tobias and Obst, Reinhard (2021): Dynamic adoption of anergy by antigen-exhausted CD4(+) T cells. In: Cell Reports, Vol. 34, No. 6, 108748

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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.

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