Sustained A2AR expression and loss paradoxically promote CD8⁺ T cell exhaustion.

Abstract

Although A2AR is a key immunoregulatory receptor that suppresses CD8⁺ T cell activation in response to elevated extracellular adenosine in inflamed or hypoxic microenvironments, its role in CD8⁺ T cell differentiation and cell-fate decisions during chronic viral infection and cancer remains poorly understood. Using A2AR-eGFP reporter mice, we show that A2AR expression is rapidly induced by TCR stimulation and persists under chronic antigen exposure and hypoxia, with sustained expression strongly associated with terminal exhaustion via the canonical Gα_s-cAMP-PKA pathway. Paradoxically, A2AR loss does not alleviate exhaustion but instead accelerates differentiation toward the terminally exhausted state. Single-cell multiomics profiling revealed that A2AR deficiency activates CD122 (IL-2Rβ)-dependent signaling, driving T cell exhaustion. Genetic deletion of CD122 in A2AR-deficient CD8⁺ T cells reduced terminal exhaustion, identifying CD122 signaling as a key mediator of A2AR loss-driven exhaustion. Intriguingly, both sustained A2AR expression and A2AR loss converge to promote T cell exhaustion differentiation through distinct mechanisms. These findings uncover a paradoxical role of A2AR in shaping CD8⁺ T cell fate choices during chronic infection and cancer.