Transfer: What Precursors Become Lung-Resistant CD4 Memory that Protect Against Respiratory Infections or Cause Lung Pathology?

What Precursors Become Lung-Resident CD4 Memory that Protect Against Respiratory Infections or Cause Lung Pathology? Respiratory viruses such as SARS-CoV1, Influenza and recently SARS-CoV2 (COVID-19) have caused the major pandemics in the 21st century and influenza causes high levels of death from yearly circulating outbreaks. T cells can target internal viral proteins, that mutate less frequently. Thus, T cell memory induced by previous vaccination or infection can still be effective against emerging mutant viral strains. Tissue resident memory (TRM) cells, that develop in the lung are at the first line of defense of our adaptive immune response against respiratory infections because of their location. However, lung CD8 TRM, which are most- studied, are short- lived. The few studies that have examined lung CD4 TRM suggest that they may decay less rapidly. Relatively little is known about lung CD4 TRM longevity and mechanisms of function, though they are known to protect against many respiratory infections such Influenza, Sendai, B.pertussis, pneumococcal pneumonia and tuberculosis infections. Moreover, it is unclear which CD4 effectors precursors become lung CD4 TRM. If CD4 lung TRM are longer-lived, they might compensate over the long-term for the rapid decline in CD8 lung TRM, thus making them good vaccine targets to provide strong more durable immunity. A majority of the CD4 and CD8 T cells in human lung express TRM features, so it is vital to understand their impact when they are reactivated during an immune response, both their positive effect on protection against pathogens and negative effects on lung function and tissue damage. In many respiratory infections such as influenza and COVID-19 there is also potential for severe lung damage leading to poor prognosis. We show that cytotoxic CD4 T cells, that are resident effectors in the lung and that contribute to damage, can be precursors of lung CD4 TRM. Thus, an understanding of how CD4 TRM can both protect and cause lung pathology on reactivation, especially if they are maintained long-term, is vital. Here, the research proposed will identify the precursors of CD4 lung TRM from CD4 lung effectors, and better define their protective and pathogenic potentials. It will phenotypically and molecularly characterize the CD4 TRM formed from subsets of lung CD4 effectors. It will study their longevity and their maintenance via mechanisms such as homeostatic proliferation and recruitment from circulation. Finally, it will study in detail their functional mechanisms of eliciting protection vs those causing lung immunopathology by direct cytolysis, inflammation andhelper function. Understanding mechanisms/conditions driving protection and pathology by CD4 TRM will enable design of interventions like vaccines and immunotherapies, that favor the development of protection while minimizing pathology. Identifying precursor CD4 effectors that give rise to protective CD4 TRM will also allow to finetune vaccine approaches that drive generation of those CD4 effector subsets. In future studies, the knowledge gained here, will allow identification of transcriptional networks that regulate the development of CD4 TRM from CD4 effectors and naïve CD4.