Long-lived highly differentiated monocyte-derived cells (LDMs) activate lung-resident CD8+ T cell memory

PROJECT SUMMARY/ABSTRACT The lung, as it is constantly challenged, has a unique immune system, much of which is still underappreciated. Respiratory viral infection, including influenza and SARS-CoV-2, is among the worst burdens of disease worldwide and in the US, and especially viral pneumonia is one of the leading causes for irreversible tissue damage and death. Importantly, immune responses of the lung to the viral infection determine the outcome of these viral illnesses, so better understanding of the lung immunology is warranted. CD8+ T cells are the most important immune effector against viral infection of the respiratory organs because they significantly reduce virus burden and spread by eliminating infected cells. But T cell immunity is not an autonomous system and innate immune cells are required for the T cells to be functional. In the lung, dendritic cells (DCs) and macrophages play such regulatory roles in general. I had previously demonstrated that tissue- infiltrated monocytes are also important for efficient T cell immune responses during influenza infection of the lung and trachea, adding to the knowledge of innate immune regulation of T cell responses. Now I have strong evidence that the monocytes infiltrating into the lung during influenza virus infection further differentiate into a novel myeloid cell type, long-lived highly differentiated monocyte-derived cell (LDM), and the LDM cells persist in the lung for many months since recovery from the infection. I also obtained preliminary, but significant, data indicating that those LDM cells are a key regulator of lung-resident memory T cell (TRM). TRM is an effective cytolytic immune effector to protect hosts from recurrent infection, however current understanding of regulatory mechanisms for lung-resident T cell memory remains insufficient. We will address an unsolved issue in this field–how lung TRM is regulated by innate immunity. In Aim 1, it will be tested if LDM, not conventional DCs, activates lung TRM upon recurrent influenza infection using a LDM depletion mouse model that I newly developed. In Aim 2, I will investigate the mechanism(s) by which the LDM activates TRM. Through rechallenge of virus-immune mice with viral antigens, reconstituted in vitro cell assays and reporter assays that distinguish cytokine signals and TCR activation signal, it will be determined if the LDM is a lung-resident antigen presenting cell (APC) type for TRM activation. In Aim 3, to corroborate evidence that the LDM promotes TRM activation, interaction, migration and tissue localization of LDM and TRM in the lung will be investigated using cutting-edge lung imaging technologies.