Establishment and recall of SARS-CoV-2 spike epitope-specific CD4+ T cell memory

Wragg and colleagues use MHC class II tetramers and TCR beta sequencing to track clonal populations of spike-specific CD4(+) cT(FH) cells from cohorts of convalescent individuals with coronavirus disease 2019 or SARS-CoV-2-vaccinated individuals over 15 months. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit CD4(+) T cell responses to the spike protein, including circulating follicular helper T (cT(FH)) cells that correlate with neutralizing antibodies. Using a novel HLA-DRB1*15:01/S-751 tetramer to track spike-specific CD4(+) T cells, we show that primary infection or vaccination induces robust S-751-specific CXCR5(-) and cT(FH) cell memory responses. Secondary exposure induced recall of CD4(+) T cells with a transitory CXCR3(+) phenotype, and drove expansion of cT(FH) cells transiently expressing ICOS, CD38 and PD-1. In both contexts, cells exhibited a restricted T cell antigen receptor repertoire, including a highly public clonotype and considerable clonotypic overlap between CXCR5(-) and cT(FH) populations. Following a third vaccine dose, the rapid re-expansion of spike-specific CD4(+) T cells contrasted with the comparatively delayed increase in antibody titers. Overall, we demonstrate that stable pools of cT(FH) and memory CD4(+) T cells established by infection and/or vaccination are efficiently recalled upon antigen reexposure and may contribute to long-term protection against SARS-CoV-2.

Automated summary

Wragg and colleagues tracked clonal populations of spike-specific CD4(+) cT(FH) cells using MHC class II tetramers and TCR beta sequencing in convalescent individuals with COVID-19 or SARS-CoV-2-vaccinated individuals. They found that both infection and vaccination induced CD4(+) T cell responses to the spike protein and that these responses correlated with neutralizing antibodies. Secondary exposure led to the recall of CD4(+) T cells with a transitory CXCR3(+) phenotype and expansion of cT(FH) cells temporarily expressing ICOS, CD38, and PD-1. The study demonstrates that stable pools of cT(FH) and memory CD4(+) T cells established by infection and/or vaccination can be efficiently recalled and may contribute to long-term protection against SARS-CoV-2.