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

Salvador Sampere-Birlanga, Stefan Klein‐Hessling, Miriam Campillo Prados, Anfei Huang, Hao Wu, Andreas Rosenwald, Wolfgang Kastenmüller, Edgar Serfling, Martin Vaeth, Friederike Berberich‐Siebelt

Persistent antigenic stimulation leads to the dysfunction of CD8 + cytotoxic T cells. These “exhausted” T EX 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 T EX 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 T EX 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 T EX 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.