How CD4 T cells protect against influenza A virus is poorly understood. Here, we address two central questions to better understand how CD4 T cells contribute to immunity during primary and secondary infection. First, we investigate the CD4 T cell-intrinsic requirements for three major transcription factors associated with an antiviral T cell phenotype (termed ‘Th1'): STAT1, STAT4, and T-bet, in directing CD4 T cell responses. We show that STAT4-deficiency does not affect the phenotype or function of wildtype or T-bet-/- CD4 T cells while STAT1-/- cells are virtually undetectable in infected host mice. Depleting NK cells rescues the STAT1-/- cells that phenocopy the compromised Th1 identity of T-bet-/- cells. Finally, we show that cytokine-mediated STAT4 activation enhances infection-induced Th1-polarization and that engaging STAT1 and STAT4 during priming dramatically improves CD4 T cell antiviral capacity. These results are relevant to T cell-based vaccine strategies aiming to promote the most efficient anti-viral T cell responses. Second, we asked the extent to which the recall of influenza-specific lung-resident memory CD4 T cells (TRM) impact the generation of new primary anti-viral T cells. TRM rapidly induce local inflammatory responses that control infection before protective T cells activated in secondary lymphoid organs reach sites of infection. Whether antigen-sensing by TRM can impact T cell priming in secondary lymphoid organs is unclear. We show that activation of influenza-primed lung TRM by antigen delivered into the airways enhances the number and activation status of antigen-bearing dendritic cells in draining lymph nodes. This accelerates the priming of naïve T cells and enhances their recruitment to the lung. Importantly, this TRM-dependent circuit enables productive T cell responses even against levels of airways antigen too low to otherwise activate naïve T cells. This adjuvant-like impact of lung TRM highlights a novel integration of local and regional T cell immunity.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2023-1063 |
| Date | 01 January 2023 |
| Creators | Finn, Caroline M |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Graduate Thesis and Dissertation 2023-2024 |
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