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

SARS-CoV-2 infection and vaccination elicit strong CD4+ T cell responses to the viral spike protein, including circulating T follicular helper (cTFH) cells that correlate with the development of neutralizing antibodies. Here we use a novel HLA-DRB1*15:01/S751 tetramer to precisely track spike-specific CD4+ T cells following recovery from mild/moderate COVID-19, after 3 doses of spike-encoding vaccines or after vaccination of previously infected individuals. Infection and primary vaccination induced robust S751-specific CXCR5- and cTFH memory responses in all individuals studied, which were distinct from a subdominant HLA-DRB1*15:01/S236-specific response in the same cohort. Across both infection and vaccination, the S751-specific response is characterised by a restricted TCR repertoire that includes a highly public clonotype. Notably, we observed recall of infection-induced TCR clones by subsequent vaccination and a high degree of clonotypic overlap between CXCR5- and cTFH populations. Overall, this study demonstrates the generation of a stable pool of cTFH and memory CD4+ T cells following infection and vaccination that are efficiently recalled upon spike antigen re-exposure, which may play an important role in long-term protection against SARS-CoV-2 infection.

Dr. Jennifer Juno is a T cell immunologist with a particular interest in T follicular helper cells and unconventional T cells. Originally from Canada, she was awarded her PhD in 2014 from the University of Manitoba, where she studied unconventional T cell dysfunction during HIV infection. Following a 2-year post-doctoral fellowship at the Public Health Agency of Canada, she moved to Melbourne to join the Peter Doherty Institute for Infection and Immunity. Jennifer now leads a team focused on harnessing specific T cell subsets to improve immunity against human infectious diseases.