The finding of pre-existing cross-reactive T cells in the airways that are able to provide rapid antiviral effector function supports their potential to maintain local sentinel surveillance to efficiently clear infection, or even abort infection before it is fully established. This underscores the potential for mucosal vaccines to induce a large reservoir of pathogen-specific airway­-resident T cells in humans. Moreover, although we could not ascertain the trigger and durability of cross-reactive T cells in BAL fluid, our data support the proposal of prior seasonal coronavirus infection as one likely source and highlight the importance of prior immune history in shaping the effectiveness of airway memory T cell cross-protection against new pathogens such as SARS-CoV-2.

A caveat of our study was the fact that donors had participated in a pneumococcal challenge and influenza vaccine trial an average of 4 months before BAL. These common ‘real-world’ exposures may have increased recruitment of SARS-CoV-2-cross­-reactive airway-resident T cells. We focused on responses to spike and RTC proteins, as these have been associated with cross-­protection and we did not have enough cells to assess the full extent of airway reactivity to SARS-CoV-2. Caution must be taken in interpreting the expression of CD69 on peptide-stimulated T cells, as it is both a residency marker and an activation marker.

We are now comparing the capacity of SARS-­CoV-2 infection and/or vaccination to expand antigen-specific T cells in human airways. In the future, it will be important to test whether nasal or aerosolized vaccines that target conserved SARS-CoV-2 regions can induce broadly cross-reactive tissue-resident T cells better able to provide rapid frontline defense against emerging variants.

Mala K. Maini and Mariana O. Diniz, University College London, London, UK.