Adaptive immunity to human coronaviruses is widespread but low in magnitude

Abstract Objectives Endemic human coronaviruses (hCoVs) circulate worldwide but cause minimal mortality. Although seroconversion to hCoV is near ubiquitous during childhood, little is known about hCoV‐specific T‐cell memory in adults. Methods We quantified CD4 T‐cell and antibody responses to hCoV spike antigens in 42 SARS‐CoV‐2‐uninfected individuals. Antigen‐specific memory T cells and circulating T follicular helper (cTFH) cells were identified using an activation‐induced marker assay and characterised for memory phenotype and chemokine receptor expression. Results T‐cell responses were widespread within conventional memory and cTFH compartments but did not correlate with IgG titres. SARS‐CoV‐2 cross‐reactive T cells were observed in 48% of participants and correlated with HKU1 memory. hCoV‐specific T cells exhibited a CCR6+ central memory phenotype in the blood, but were enriched for frequency and CXCR3 expression in human lung‐draining lymph nodes. Conclusion Overall, hCoV‐specific humoral and cellular memory are independently maintained, with a shared phenotype existing among coronavirus‐specific CD4 T cells. This understanding of endemic coronavirus immunity provides insight into the homeostatic maintenance of immune responses that are likely to be critical components of protection against SARS‐CoV‐2.