Persistent High Percentage of HLA-DR(+)CD38(high) CD8(+) T Cells Associated With Immune Disorder and Disease Severity of COVID-19

BACKGROUND: The global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR(+)CD38(+) CD8(+) T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38(+)HLA-DR(+) CD8(+) T population was reported to play contradictory roles in SARS-CoV-2 infection. METHODS: A total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3–7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally. RESULTS: We revealed that the HLA-DR(+)CD38(+) CD8(+) T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR(+)CD38(dim) and HLA-DR(+)CD38(hi). We observed a persistent accumulation of HLA-DR(+)CD38hi CD8(+) T cells in severe COVID-19 patients. These HLA-DR(+)CD38(hi) CD8(+) T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR(+)CD38(dim) CD8(+) T cells. Moreover, the clinical and laboratory data supported that only HLA-DR(+)CD38(hi) CD8(+) T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients. CONCLUSIONS: Our findings indicated that HLA-DR(+)CD38(hi) CD8(+) T cells were correlated with disease severity of COVID-19 rather than HLA-DR(+)CD38(dim) population.