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

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.