Persistent CD4+ T cell hyporesponsiveness during recovery from prolonged symptomatic SARS-CoV-2 infection

Symptoms of acute SARS-CoV-2 infection often resolve quickly but are sometimes associated with persistent immune dysfunction. The factors that predispose individuals to compromised immune function have not been well defined. We investigated CD4 + T cell phenotype and function in a small cohort of individuals who recovered from mild to moderate SARS-CoV-2 infection without hospitalization and were divided into short or prolonged symptom duration groups. Five individuals with prolonged symptom duration showed marked downregulation of CD4 on CD3 + CD8 − T cells (CD4 low group) and a poor response to TCR stimulation with the superantigen Staphylococcal enterotoxin B (SEB), as shown by weak upregulation of the activation markers CD134, CD25, CD279, and CD69. CD4 surface intensities recovered to normal levels in four of these individuals within 3–12 months. Selected cytokines (IL-1RA, IL-7, and VEGF) were elevated in individuals with low CD4, but plasma levels of anti-S1 IgG did not correlate with CD4 hyporesponsiveness. Bulk RNA sequencing of unstimulated and SEB-treated CD3 + CD8 − T cells revealed a > 50% reduction in the number of differentially expressed genes in the CD4 low group compared to the same individuals after CD4 levels were recovered and a healthy control group. Analyses of differentially expressed genes in unstimulated CD4 low cells suggested a response to IFN, while SEB-stimulated CD4 low cells showed reduced functionality of T cell activation, differentiation, and glycolysis pathways. In summary, in some individuals, prolonged symptomatic recovery from SARS-CoV-2 infection was associated with evidence of IFN signaling and transient reduction in CD4 expression accompanied by attenuated TCR activation by SEB.