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

The University of Rochester received a $415,250 Project Grant award from the National Institute of Allergy and Infectious Diseases under the Allergy and Infectious Diseases Research program (CFDA 93.855) on July 7, 2025, with a completion date of June 30, 2027. The award supports investigator-initiated biomedical research focused on understanding the immunological mechanisms of viral respiratory infections, specifically examining how long-lived highly differentiated monocyte-derived cells (LDMs) regulate lung-resident CD8+ T cell memory responses. The research addresses critical gaps in lung immunology relevant to influenza and SARS-CoV-2 infections, with the ultimate objective of improving outcomes in viral pneumonia cases by clarifying innate immune regulation of protective T cell immunity in respiratory tissues.

The primary deliverable under this award is peer-reviewed scientific research advancing knowledge of disease mechanisms in infectious respiratory diseases. The project will generate experimental data, scientific publications, and potentially new therapeutic insights regarding the role of monocyte-derived cells in establishing long-term protective immune memory in the lungs. This research contributes to the federal program's mission of supporting investigator-initiated projects that advance scientific knowledge of infectious and immunologic diseases and improve health outcomes against emerging disease threats.

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.