Persistent CD4 T cell functional deficits in individuals recovered from prolonged symptomatic SARS-CoV-2 infection

Abstract We assessed phenotypic changes in CD4 +T cells in 17 individuals (male and female, age 26–71, not hospitalized) after recovery from moderate SARS-CoV-2 infection. A subset of 5 individuals with protracted symptom duration showed marked downregulation of CD4 on CD3 +CD8 −T cells and a poor response to TCR stimulation with SEB, as judged by failure to upregulate activation markers CD134, CD25 and CD69. This defective response (DR) group included 3 subjects sampled <30 days and 2 sampled >150 days post-recovery. In longitudinal samples obtained 3–12 months later, 4 of 5 individuals harbored T cells showing a recovered response (RR), with CD4 levels comparable to normal response (NR) healthy controls. One individual did not show a recovered response until 10 mo later. Levels of anti-S1 IgG did not correlate with the CD4 defect. Selected plasma cytokines (IL-1RA, APRIL, VEGF) elevated in the DR group correlated with low CD4 levels. The SEB activation program, defined as genes differentially expressed (DE) between paired unstimulated and stimulated CD3 +CD8 −T cells, showed a >50% reduction in the number of DE genes in the DR group compared to the RR and NR groups. Upstream driver analysis of genes uniquely DE in the NR and RR groups, representing a recovered/normal activation program, showed strongly reduced influence of VEGF. Conversely, similar analysis of genes uniquely DE in the DR group showed reduced influence of TCR signaling. In sum, recovery from prolonged symptomatic Covid-19 is often associated with a global CD4 +T cell response defect, defined by low surface CD4 and defective T cell activation at the transcriptional level, and correlating with elevated cytokines such as VEGF associated with severe or long Covid-19. Supported by NIH U19 AI062629