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. We know
relatively little 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, we know little about the CD4 effectors that are precursors to the 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
oflung CD4 TRM. Thus, it is vital that we learn how CD4 TRM can both protect and cause lung pathology on
reactivation, especially if they are maintained long-term.
Here, we propose to identify the precursors of CD4 lung TRM from CD4 lung effectors, and better define their
protective and pathogenic potentials. We will phenotypically and molecularly characterize the CD4 TRM formed
from subsets of lung CD4 effectors. We will study their longevity and their maintenance via mechanisms such
as homeostatic proliferation and recruitment from circulation. Finally, we will study in detail their functional
mechanisms of eliciting protection vs those causing lung immunopathology by direct cytolysis, inflammation and
helper 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 us
to finetune vaccine approaches that drive generation of those CD4 effector subsets. In future studies, we will
use the knowledge gained here, to identify transcriptional networks that regulate the development of CD4 TRM
from CD4 effectors and naïve CD4.
