Respiratory viral infections are a leading cause of mortality, causing an estimated two million deaths per year [1]. Respiratory viruses can cause catastrophic viral pandemics evidenced by the 1918 H1N1 pandemic and the current COVID-19 pandemic, which have claimed more than 40 and 6 million lives, respectively 2, 3. Long-term protection against reinfection by the same or similar viruses is mediated by memory T and B cells, as well as antibodies produced by long-lived plasma cells. Pathogens such as influenza virus and SARS-CoV-2 have the ability to change their surface antigens frequently, escaping antibody-mediated viral neutralization. In this case, memory T cells are believed to play a crucial role in providing effective protection against viral dissemination and the development of severe diseases [4].

The respiratory mucosal interface is the front line encountering pathogens that spread via airborne transmission. Following infection, a subset of memory T cells termed tissue-resident memory T (TRM) cells, are retained in the respiratory tract. TRM cells are phenotypically and functionally different from the circulating central memory T (TCM) and effector memory T (TEM) cells [5]. Numerous reports have already demonstrated that compared with the circulating TCM and TEM cells, TRM (both CD4+ and CD8+) plays a pivotal, if not dominant, role in the protection against secondary viral infection in the respiratory tract [5]. As the local sword, TRM cells rapidly respond upon pathogen invasion, killing virus-infected cells directly and activating a series of downstream immune events to impede viral replication and dissemination. Despite the important roles of TRM cells in protection against respiratory infection and reinfection, induction of strong antigen-specific TRM cells is not usually exploited by most available or candidate vaccines. It is thus needed to make more efforts on the development of TRM-based mucosal vaccines against the infection and transmission of respiratory viruses, in particular influenza and SARS-CoV-2 [6]. In the following sections, we will mainly focus on the regulation and protective functions of CD8+ and CD4+ TRM in the contexts of influenza and SARS-CoV-2 natural infections or vaccinations.