We detected significantly higher frequencies of phenotypically exhausted SARS-CoV-2-specific CD4+ T cells in unvaccinated symptomatic COVID-19 patients with high severity scores (i.e., patients with severity 3, 4, and 5) compared to unvaccinated asymptomatic COVID-19 patients (i.e., patients with severity 0) (Figure 5A—up to ∼6.9-fold increase for ORF612–26-specific PD-1+TIGIT+CD4+ T cells and up to ∼7.8-fold increase for M176–190-specific TIM-3+CTLA-4+CD4+ T cells). Here, HAVCR2 is linked to COVID-19.