Non-redundant functions of NFATc1 in survival and NFATc2 in generation of exhausted CD8+ T cells.

Persistent antigenic stimulation leads to the dysfunction of CD8+ cytotoxic T cells. These "exhausted" TEX cells exhibit reduced proliferative capacity, impaired effector function, and increased expression of co-inhibitory receptors. Chronic antigen receptor stimulation induces the expression of NFATc1/αA, a short isoform of NFATc1 that promotes TEX cell survival. The induction of NFATc1/αA is accompanied by a significant decrease in NFATc2 expression. NFATc2 limits the expression of stemness-associated genes, such as Tcf7, Sell, and Id3. It also supports the expression of Prf1, Gzmb, and the TEX marker gene Havcr2. Therefore, ablation of NFATc2 mitigates functional exhaustion of CD8+ T cells during chronic viral infection and antitumor immunity. Our findings illustrate that NFATc1 promotes the survival of TEX cells, while NFATc2 promotes the terminal differentiation and dysfunction of exhausted CD8+ T cells. The data suggest a non-redundant interplay between NFATc1 and NFATc2, each playing a distinct role in controlling CD8+ T-cell exhaustion. These findings open novel avenues to enhance the efficacy of immune checkpoint and CAR T-cell therapies.