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

Kathleen M. Wragg, Wen Shi Lee, Marios Koutsakos, Hyon-Xhi Tan, Thakshila Amarasena, Arnold Reynaldi, Grace Gare, Penny Konstandopoulos, Kirsty R. Field, Robyn Esterbauer, Helen E. Kent, Miles P. Davenport, Adam K. Wheatley, Stephen J. Kent, Jennifer A. Juno

Research output: Contribution to journalArticleResearchpeer-review

31 Citations (Scopus)


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 (cTFH) cells that correlate with neutralizing antibodies. Using a novel HLA-DRB1*15:01/S751 tetramer to track spike-specific CD4+ T cells, we show that primary infection or vaccination induces robust S751-specific CXCR5 and cTFH cell memory responses. Secondary exposure induced recall of CD4+ T cells with a transitory CXCR3+ phenotype, and drove expansion of cTFH 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 cTFH 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 cTFH 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.

Original languageEnglish
Pages (from-to)768-780
Number of pages13
JournalNature Immunology
Issue number5
Publication statusPublished - May 2022

Cite this