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

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 Gαs–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.