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.