Clonally diverse CD38⁺HLA-DR⁺CD8⁺ T cells persist during fatal H7N9 disease

Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8⁺ T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38⁺HLA-DR⁺PD-1⁺ CD8⁺ T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-αβ analyses of activated CD38⁺HLA-DR⁺CD8⁺ T cells show similar TCRαβ diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38⁺HLA-DR⁺CD8⁺ T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38⁺HLA-DR⁺CD8⁺ T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRαβ clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease.