Persistent High Percentage of HLA-DR+CD38high CD8+ T Cells Associated With Immune Disorder and Disease Severity of COVID-19

Abstract

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.

Keywords: CD38; COVID-19; HLA-DR; immune disorder; severity.