Platelets modulate CD4⁺ T-cell function in COVID-19 through a PD-L1 dependent mechanism

Severe COVID-19 is associated with a systemic inflammatory response and progressive CD4⁺ T-cell lymphopenia and dysfunction. We evaluated whether platelets might contribute to CD4⁺ T-cell dysfunction in COVID-19. We observed a high frequency of CD4⁺ T cell-platelet aggregates in COVID-19 inpatients that inversely correlated with lymphocyte counts. Platelets from COVID-19 inpatients but not from healthy donors (HD) inhibited the upregulation of CD25 expression and tumour necrosis factor (TNF)-α production by CD4⁺ T cells. In addition, interferon (IFN)-γ production was increased by platelets from HD but not from COVID-19 inpatients. A high expression of PD-L1 was found in platelets from COVID-19 patients to be inversely correlated with IFN-γ production by activated CD4⁺ T cells cocultured with platelets. We also found that a PD-L1-blocking antibody significantly restored platelets' ability to stimulate IFN-γ production by CD4⁺ T cells. Our study suggests that platelets might contribute to disease progression in COVID-19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4⁺ T cells functionality.