Inhibition of programmed cell death-1 in cytotoxic CD8+ T cells exacerbates pressure overload-induced cardiac injury

Methods

To evaluate the effects of anti-PD-1 antibody on transverse aortic constriction (TAC)-induced cardiac remodeling and HF, anti-PD-1 antibody-treated mice, T cell-, myeloid-, and CD8+ T cell-specific PD-1 knockout (KO) mice, and C-X-C motif chemokine receptor 3 (CXCR3) KO and granzyme B (GZMB) KO mice combined with flow cytometry, western blotting, immunofluorescence staining, pharmacological approaches, and bulk RNA-sequencing analyses were used.

Results: Administration of anti-PD-1 antibody, T cell-, or CD8+ T cell-specific PD-1 deletion, but not myeloid-specific PD-1 KO, aggravated TAC-induced cardiomyopathy and HF in mice. Mechanistically, PD-1 blockade or deletion increased myocardial infiltration of CXCR3+ CD8+ T cells, which led to GZMB/perforin-mediated impairment of cardiomyocyte mitochondrial complex I to exacerbate TAC-induced cardiac injury and HF. Notably, TAC-enhanced chemotaxis, between cardiac fibroblasts (CF)-derived CXCL9/CXCL10 and CXCR3+ CD8+ T cells, was a driving force for recruiting CXCR3+ CD8+ T cells under the conditions of PD-1 blockade or deletion.

The worsened TAC-induced cardiomyopathy caused by anti-PD-1 antibody or T cell-specific PD-1 deletion was rescued by genetic deletion or pharmacological blockade of GZMB and CXCR3. Conclusions: Anti-PD-1 antibody administration enhances myocardial infiltrated CXCR3+ CD8+ T cells under TAC condition via CXCL9/CXCL10-mediated chemotaxis. These CD8+ T cell-released GZMB impairs mitochondrial complex I and causes cardiomyocytes apoptosis in a perforin-dependent manner, exacerbating TAC-induced cardiomyopathy and HF.

CXCL9/CXCL10-CXCR3+ CD8+ T cell axis may represent a promising target for combating anti-PD-1 antibody-associated cardiotoxicity.