Nasal epithelial tissue of the upper respiratory tract is the first site of contact by inhaled pathogens such as influenza virus. We show that this region is key to limiting viral spread to the lower respiratory tract and associated disease pathology. Immunization of the upper respiratory tract leads to the formation of local tissue-resident memory CD8⁺ T cells (Trm cells). Unlike Trm cells in the lung, these cells develop independently of local cognate antigen recognition and transforming growth factor–β signaling and persist with minimal decay, representing a long-term protective population. Repertoire characterization revealed unexpected differences between lung and nasal tissue Trm cells, the composition of which was shaped by the developmental need for lung, but not nasal, Trm cells to recognize antigen within their local tissue. We show that influenza-specific Trm cells in the nasal epithelia can block the transmission of influenza virus from the upper respiratory tract to the lung and, in doing so, prevent the development of severe pulmonary disease. Our findings reveal the protective capacity and longevity of upper respiratory tract Trm cells and highlight the potential of targeting these cells to augment protective responses induced to respiratory viral vaccines.

The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8⁺ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific CD8⁺ Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of CD8⁺ Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus–specific CD8⁺ T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific CD8⁺ T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza–specific CD8⁺ Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other CD8⁺ T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants.

Tissue-resident memory T (Trm) cells are described as having a "sensing and alarming" function, meaning they can rapidly release cytokines in response to local cognate antigen recognition, which in turn, draws circulating immune cells into the tissue. Here, we show noncognate, bystander activation can also trigger the sensing and alarming function of pulmonary CD8+ Trm cells. Virus-specific CD8+ Trm cells lodged in the lung parenchyma, but not memory CD8+ T cells located in the vasculature, rapidly synthesize interferon γ (IFN-γ) following the inhalation of heat-killed bacteria or bacterial products, a process driven by interleukin-12 (IL-12)/IL-18 exposure. We show that a respiratory bacterial infection leads to bystander activation of lung Trm cells that boosts neutrophil recruitment into the airways and attenuates the severity of bacterial pneumonia. These data reveal that lung Trm cells have innate-like properties, enabling amplification of inflammation and participation in noncognate responses to bacterial infections.

The lymphoid tissue that drains the upper respiratory tract represents an important induction site for cytotoxic T lymphocyte (CTL) immunity to airborne pathogens and intranasal vaccines. Here, we investigated the role of the nasal-associated lymphoid tissues (NALTs), which are mucosal-associated lymphoid organs embedded in the submucosa of the nasal passage, in the initial priming and recall expansion of CD8⁺ T cells following an upper respiratory tract infection with a pathogenic influenza virus and immunization with a live attenuated influenza virus vaccine. Whereas NALTs served as the induction site for the recall expansion of memory CD8⁺ T cells following influenza virus infection or vaccination, they failed to support activation of naïve CD8⁺ T cells. Strikingly, NALTs, unlike other lymphoid tissues, were not routinely surveyed during the steady state by circulating T cells. The selective recruitment of memory T cells into these lymphoid structures occurred in response to infection-induced elevation of the chemokine CXCL10, which attracted CXCR3⁺ memory CD8⁺ T cells. These results have significant implications for intranasal vaccines, which deliver antigen to mucosal-associated lymphoid tissue and aim to elicit protective CTL-mediated immunity.

Influenza A virus is highly contagious, infecting 5–15% of the global population every year. It causes significant morbidity and mortality, particularly among immunocompromised and at-risk individuals. Influenza virus is constantly evolving, undergoing continuous, rapid, and unpredictable mutation, giving rise to novel viruses that can escape the humoral immunity generated by current influenza virus vaccines. Growing evidence indicates that influenza-specific T cells resident along the respiratory tract are highly effective at providing potent and rapid protection against this inhaled pathogen. As these T cells recognize fragments of the virus that are highly conserved and less prone to mutation, they have the potential to provide cross-strain protection against a wide breadth of influenza viruses, including newly emerging strains. In this review, we will discuss how influenza-specific memory T cells in the lung are established and maintained and how we can harness this knowledge to design broadly protective influenza A virus vaccines.