MAIT cells activate dendritic cells to promote TFH cell differentiation and induce humoral immunity

Protective immune responses against respiratory pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, are initiated by the mucosal immune system. However, most licensed vaccines are administered parenterally and are largely ineffective at inducing mucosal immunity. The development of safe and effective mucosal vaccines has been hampered by the lack of a suitable mucosal adjuvant. In this study we explore a class of adjuvant that harnesses mucosal-associated invariant T (MAIT) cells. We show evidence that intranasal immunization of MAIT cell agonists co-administered with protein, including the spike receptor binding domain from SARS-CoV-2 virus and hemagglutinin from influenza virus, induce protective humoral immunity and immunoglobulin A production. MAIT cell adjuvant activity is mediated by CD40L-dependent activation of dendritic cells and subsequent priming of T follicular helper cells. In summary, we show that MAIT cells are promising vaccine targets that can be utilized as cellular adjuvants in mucosal vaccines. [Display omitted] •Mucosal vaccination using MR1 ligands as adjuvants protects from virus challenge•MAIT cell activation drives production of IgG and IgA against targeted antigens•MAIT cells induce humoral immunity via dendritic cell activation to prime TFH cells•CD40-CD40L interactions underpin MAIT cell-mediated dendritic cell activation Respiratory pathogens remain a major cause of mortality globally, and there is a significant need for mucosal vaccines. Pankhurst et al. show that MAIT cell agonists can function as mucosal adjuvants that promote protective virus-specific immunity against influenza and SARS-CoV-2.