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Principal Investigator: THOMAS S. KUPPER
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $993,763
Funding agency: National Institute of Allergy and Infectious Diseases
Respiratory viral pathogens have been responsible for major pandemics over the past two centuries with
extraordinary human and economic cost. While most vaccines have focused on antibody neutralization of
virus, there has been growing interest in targeting CD8 T cell immunity for more durable protective immune
memory. Specifically, there has been interest in vaccines that generate tissue resident memory T cells (TRM),
but one issue complicating this approach is the observed lack of durability of lung TRM, whether generated by
pulmonary viral infection or targeted vaccination. Unlike TRM in other tissues, which accumulate and survive for
years, lung TRM have half-lives measured in days. We have discovered an alternative population of CD8 TM that
can mediate lung-focused T cell memory and protection from morbidity and mortality after skin vaccination.
The durability of this immunity appears to be provided by a unique population of lung tropic CD8 T cells
concentrated in the intravascular space of the lung (rather than the parenchyma). Using IAV as a model viral
respiratory pathogen, these CD8 T cells appear to rapidly extravasate and enter lung parenchyma within hours
after infection, providing a rapid on demand protective memory response with kinetics comparable to lung TRM.
Their activity does not require CD4 T cells, and elimination of these CD8 TM cells completely abrogates robust
vaccine protection. Analysis of these cells by scRNAseq reveals that they have circulatory markers, but also
immediate-early genes reminiscent of skin TRM generated from the same vaccination. They are transcriptionally
distinct from spleen TEM and LN TCM generated by the same vaccination and appear to be robust >6 months
later. Most importantly, they provide complete protection from morbidity and mortality from viral lung challenge
and function independently of antibodies and B cells. Using defined genetic models, scRNA seq, ATACseq,
multidimensional flow cytometry, and lung intravital microscopy, we will test key hypotheses about the mode of
generation, in vivo biological behavior, and protective immunity of these cells. We have assembled expert
collaborators in each of these areas to fully explore the biology of these cells and the potential of generating
these cells by epidermal disruption (ed) vaccination. We believe that these TM cells are an important and
unstudied component of normal T cell memory designed to provide superior and long-lasting lung immunity
without occupying valuable lung parenchymal space. We believe that optimized generation of these cells by
improved vaccination approaches will provide a superior way to combat respiratory viral pathogens.
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