PARP1-NFATc1-PD1 pathway of maturation and stability of CD8+T cells is beneficial against chronic Trypanosoma cruzi infection

Poly(ADP-ribose) polymerase 1 (PARP1) inhibition improved the ventricular function in Chagas disease (CD). Here, we uncovered that <i>Parp1</i> depletion enhances cardiac health by regulating CD8⁺T cell response against <i>Trypanosoma cruzi</i> (<i>Tc</i>) infection. For this, <i>Parp1</i> ^-/- and wild-type (WT) mice were challenged with <i>Tc</i> and euthanized at acute and chronic phases of parasite replication and CD development, respectively. <i>Parp1</i> ^-/- mice controlled the chronic parasite persistence and associated inflammatory pathology more effectively than WT mice. <i>Parp1</i> ^-/- enhanced the maturation and stability of metabolically reprogrammed CD8⁺ effector and memory T cells with increased cytotoxic effects against the parasite. Mechanistically, PARP1 depletion enhanced the NFATc1 translocation to Pdcd1 promoter in CD8⁺T cells, altered the PD1:PDL1 stoichiometric ratio between CD8⁺T and antigen-presenting cells, and promoted CD8⁺T cell longevity and function during chronic <i>Tc</i> infection. We conclude that molecular and chemical inhibitors of PARP1 would offer a potential therapy to arrest CD pathogenesis.