P2RX7 programs checkpoint-responsive exhausted CD8+ T cell states through a KLF3 metabolic circuit
Year: 2026
Type: preprint
Abstract: Checkpoint-responsive exhausted CD8 + T cells sustain immunity during chronic infection and cancer, but the tissue-derived signals that preserve these cells remain poorly defined. Here, we identify extracellular ATP sensing through P2RX7 as a microenvironmental circuit that maintains progenitor exhausted (T PEX ) and tissue-resident exhausted (TR TEX ) CD8 + T cells. P2RX7 was enriched in T PEX and TR TEX cells and was required cell-intrinsically to preserve their abundance, diversity, and developmental competence during chronic viral infection. Loss of P2RX7 restricted early progenitor trajectories and induced mitochondrial dysfunction, lipid peroxidation, and terminal exhaustion-associated phenotypes. Mechanistically, P2RX7-dependent Ca 2+ influx activated NFAT/AP-1 signaling, which induced KLF3 to promote mitochondrial fitness, subset development, and persistence of T PEX and TR TEX cells. P2RX7 also supported CD8 + T cell expansion after PD-1 blockade, whereas pharmacologic P2RX7 activation enhanced antitumor immunity in preclinical models. These findings define an extracellular ATP-P2RX7-KLF3 program that couples tissue damage sensing to metabolic adaptation and persistence of checkpoint-responsive exhausted CD8 + T cells.
Source: Research Square
Authors: Henrique Borges da Silva, Caio Salgado, Leticia Kogachi, Guilherme Souza-Silva, Igor Santiago-Carvalho, Haiguang Wang, Changwei Peng, Bruna Macedo, Constantine Yerocostas, Jian Shen, Kexin Gai, Olivia Liseth, Angad Beniwal, Dustin Grief, Nhan Tran, Richard Vile, Bryan Husta, John Copland, J. Justin Milner, Stephen Jameson, Weiguo Cui
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225744352