SARS-CoV-2 epitope-specific CD4⁺ memory T cell responses across COVID-19 disease severity and antibody durability

CD4⁺ T cells are central to long-term immunity against viruses through the functions of T helper 1 (T_H1) and T follicular helper (T_FH) cell subsets. To better understand the role of these subsets in coronavirus disease 2019 (COVID-19) immunity, we conducted a longitudinal study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4⁺ T cell and antibody responses in convalescent individuals who seroconverted during the first wave of the pandemic in Boston, MA, USA, across a range of COVID-19 disease severities. Analyses of spike (S) and nucleocapsid (N) epitope-specific CD4⁺ T cells using peptide and major histocompatibility complex class II (pMHCII) tetramers demonstrated expanded populations of T cells recognizing the different SARS-CoV-2 epitopes in most individuals compared with prepandemic controls. Individuals who experienced a milder disease course not requiring hospitalization had a greater percentage of circulating T_FH (cT_FH) and T_H1 cells among SARS-CoV-2-specific cells. Analysis of SARS-CoV-2-specific CD4⁺ T cells responses in a subset of individuals with sustained anti-S antibody responses after viral clearance also revealed an increased proportion of memory cT_FH cells. Our findings indicate that efficient early disease control also predicts favorable long-term adaptive immunity.