Lung tissue-resident memory T cells: the gatekeeper to respiratory viral (re)-infection

Abstract

The discovery of lung tissue-resident memory T (T_RM) cells and the elucidation of their function in antiviral immunity have inspired considerable efforts to leverage the power of T_RM cells, in defense to the infections and reinfections by respiratory viruses. Here, we have reviewed lung T_RM cell identification, molecular regulation, and function after influenza and SARS-CoV-2 infections. Furthermore, we have discussed emerging data on T_RM responses induced by systemic and mucosal vaccination strategies. We hope that our current outstanding of T_RM cells in this review could provide insights toward the development of vaccines capable of inducing highly efficacious mucosal T_RM responses for protection against respiratory viral infections.

Figure 1.. Lung T_RM cell generation, maintenance and function.

After respiratory viral infection (such as influenza and SARS-CoV-2) or intranasal vaccination, dendritic cells carrying viral antigen migrate from lung to draining mediastinal lymph nodes (mLNs), where naive T cells are activated. Primed effector T cells then egress from the mLNs and migrate to the lung for viral clearance. During this process, T_RM precursors highly express transcriptional factors Blimp1, Hobit, Runx3, Bhlhe40 and Notch, while downregulate KLF2, T-bet, Eomes and TCF1. As a result, CD69, CD103 (selectively) and CXCR3 are upregulated to assist T_RM cells localization and retention in the lung. In addition, CXCR6 expression further promotes T_RM cell localization into the airway. In this context, CD4₊ T_RM cells can differentiate into IFN-γ- producing CD4₊ T_RM1 and IL-21-producing CD4₊ T_RH cells, with the latter help IFN-γ-producing CD8₊ T_RM cell maintenance and local B cell responses. CD8₊ T_RM cells can also kill the infected cells.