Protective memory CD4 T cell responses against influenza A virus (IAV) involve a diverse array of cell types
with unique characteristics. An emerging axis of heterogeneity is the division between lung tissue-resident
memory (TRM) and conventional memory cells that circulate through secondary lymphoid organs. Most studies
to date have focused on characterizing the anti-viral activities of these subsets in isolation during recall
responses. Our preliminary studies, however, support the concept that synergies between regional and systemic
memory cells are a vital and uncharacterized aspect of highly effective CD4 T cell responses. Our work also
indicates that such integrated responses can be optimized to improve viral control and to reduce
immunopathology by promoting different functions in TRM versus in conventional memory CD4 cells. This
proposal will provide novel mechanistic insight into how vaccines can maximize synergies between local and
systemic CD4 memory cells to improve vaccine-induced protection against IAV.
We will optimize models to reconstitute naive mice with separate populations of well characterized lung TRM
and/or conventional memory CD4 cells primed by IAV. This experimental system will facilitate clear analysis of
how TRM responses impact the re-activation and subsequent response parameters of systemic memory CD4
cells upon IAV infection. Our models will also allow for modulation of the numbers and functional capacities of
the cells within each memory compartment in order to identify unique subset-specific correlates of protection.
We will also specifically deplete CD4 TRM in IAV-immune mice, thus allowing further characterization of local and
systemic memory CD4 synergy during heterosubtypic infection in intact, vaccinated mice.
In Aim 1, we will test the hypothesis that lung CD4 TRM activation within the first few days of IAV infection
increases efficiency of antigen presentation in secondary lymphoid organs, leading to the more rapid recall of
conventional memory CD4 cells. We will also determine if TRM reduce the magnitude of conventional memory
responses through their earlier control of viral titers and inflammation in the lung. In Aim 2, we will determine
how the integrated memory CD4 response affects key parameters of IAV clearance and collateral damage
versus in mice reconstituted with either memory subset alone. Finally, we will determine if synergistic CD4
protection against IAV can be improved by restricting prototypical T-bet-dependent Th1 programming to only the
TRM subset. This work will provide a mechanistic framework to improve CD4 T cell-dependent protection against
IAV and other pathogens and optimize innovative experimental systems to facilitate future discovery.