TNFα-producing CD4+ T cells dominate the SARS-CoV-2-specific T cell response in COVID-19 outpatients and are associated with durable antibodies

SARS-CoV-2-specific CD4+ T cells are likely important in immunity against COVID-19, but our understanding of CD4+ longitudinal dynamics following infection and specific features that correlate with the maintenance of neutralizing antibodies remains limited. We characterized SARS-CoV-2-specific CD4+ T cells in a longitudinal cohort of 109 COVID-19 outpatients. The quality of the SARS-CoV-2-specific CD4+ response shifted from cells producing IFN{gamma} to TNF+ from five days to four months post-enrollment, with IFN{gamma}-IL21-TNF+ CD4+ T cells the predominant population detected at later timepoints. Greater percentages of IFN{gamma}-IL21-TNF+ CD4+ T cells on day 28 correlated with SARS-CoV-2 neutralizing antibodies measured seven months post-infection ({rho}=0.4, P=0.01). mRNA vaccination following SARS-CoV-2 infection boosted both IFN{gamma} and TNF producing, spike protein-specific CD4+ T cells. These data suggest that SARS-CoV-2-specific, TNF-producing CD4+ T cells may play an important role in antibody maintenance following COVID-19.

Long Term Accuracy of SARS-CoV-2 Interferon-γ Release Assay and its Application in Household Investigation

BackgroundAn immunodiagnostic assay that sensitively detects a cell-mediated immune response to SARS-CoV-2 is needed for epidemiological investigation and for clinical assessment of T cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses. MethodsThe performance of a whole blood interferon-gamma (IFN-{gamma}) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific CD4 and CD8 T cells was evaluated in COVID-19 convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen. ResultsThe overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI] 79.0-89.0) and 86.6% (123/142; 95% CI;80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI 64.4-89.2) at 10 months post-infection (P<0.01). The IFN-{gamma} response remained relatively robust at 10 months post-infection (3.8 vs. 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of +50% (95% CI +25.4-+74.6) and +21.7% (95% CI, +9.23-+42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts. ConclusionsThe SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2. Key pointsSARS-CoV-2 immunodiagnostics are needed to identify infected individuals in order to understand the transmission dynamics of emerging variants and to assess vaccine response. Interferon-gamma release assay maintains sensitivity 10 months post-infection in convalescents and detects more household contacts than IgG.