Exhausted/senescent CD4⁺ T cells as predictors of vaccine failure and severe coronavirus disease 2019 in solid organ transplant recipients

Despite booster vaccinations, solid organ transplant (SOT) recipients develop suboptimal immunity and remain at risk of severe coronavirus disease 2019 (COVID-19). Chronic immunosuppression and repeated antigen exposure favor T cell exhaustion/senescence, potentially challenging the development of protective immunity. In a prospective multicenter study including 80 naïve SOT patients receiving 5 severe acute respiratory syndrome coronavirus 2 mRNA-based vaccine doses, exhausted/senescent T cell phenotypes were longitudinally profiled at distinct time points, and their impact on antigen-specific immune responses was assessed by antibodies, memory B cells, cytokine-producing T cells, and activation-induced markers on CD4 and CD8 T cells. We observed wide heterogeneity of vaccine-induced adaptive immunity across compartments. T cell exhaustion/senescence did not change after 3 vaccine doses. Notably, high percentages of CD57⁺, CD57⁺PD1⁺, programmed cell death protein 1 (PD1)⁺, and CD57⁺TIM3⁺ exhausted/senescent CD4 T cells at baseline independently predicted poor adaptive functional immune responses despite multiple boosters, regardless of SOT type and immunosuppressive regimen (area under the curve 0.89, 95% confidence interval 0.81-0.97, sensitivity 0.79, specificity 0.92). Such phenotypes were predominantly observed among tacrolimus/mycophenolate-based regimens. Moreover, SOT recipients with high percentages of CD57⁺, CD57⁺PD1⁺, and CD57⁺TIM3⁺ exhausted/senescent CD4 T cells at baseline predicted severe COVID-19 (area under the curve 0.88, P < .01). Our study adds preliminary new insight in the field and has clinical implications for risk-stratification against COVID-19 and other viral infections, ultimately guiding decision-making for establishing preventive strategies in SOT patients.