Examining Novel Aspects of T-cell Priming and Lung Resident T-cell Function to Improve Vaccine Induced Protection Against Influenza A Virus

Author

Caroline M. Finn, University of Central FloridaFollow

Keywords

T-cell, CD4, Influenza, tissue resident memory, STAT1, STAT4, lung

Abstract

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 (T_RM) impact the generation of new primary anti-viral T cells. T_RM 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 T_RM can impact T cell priming in secondary lymphoid organs is unclear. We show that activation of influenza-primed lung T_RM 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 T_RM-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 T_RM highlights a novel integration of local and regional T cell immunity.

Completion Date

2023

Semester

Fall

Committee Chair

McKinstry, Karl Kai

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

application/pdf

Identifier

DP0028448

Language

English

Release Date

June 2027

Length of Campus-only Access

3 years

Access Status

Doctoral Dissertation (Campus-only Access)

STARS Citation

Finn, Caroline M., "Examining Novel Aspects of T-cell Priming and Lung Resident T-cell Function to Improve Vaccine Induced Protection Against Influenza A Virus" (2023). Graduate Thesis and Dissertation 2023-2024. 243.
https://stars.library.ucf.edu/etd2023/243