Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion
Kaili Ma, Lina Sun, Mingjing Shen, Xin Zhang, Zhen Xiao, Jiajia Wang, Xiaowei Liu, Kanqiu Jiang, F. Xiao‐Feng Qin, Feng Guo, Baojun Zhang, Lianjun Zhang
Abstract
Exhausted CD8+ T cells with limited effector functions and high expression of multiple co-inhibitory receptors are one of the main barriers hindering antitumor immunity. The NADase CD38 has received considerable attention as a biomarker of CD8+ T cell exhaustion, but it remains unclear whether the increased CD38 directly promotes T cell dysfunctionality. Here, we surprisingly found that although Cd38 deficiency partially reverses NAD+ degradation and T cell dysfunction in vitro, the terminal exhausted differentiation of adoptively transferred CD8+ T cells in tumor is not impacted by either deficiency or overexpression of CD38. Monitoring the dynamic NAD+ levels shows that NAD+ levels are comparable between tumor infiltrated WT and Cd38−/− CD8+ T cells. Therefore, our results suggest that decreased NAD+ are correlated with T cell dysfunction, but deficiency of CD38 is not enough for rescuing NAD+ in tumor infiltrated CD8+ T cells and fails to increase the efficacy of antitumor T cell therapy.