Date of Award

Spring 5-15-2026

Degree Type

Dissertation

Degree Name

PhD Molecular Bioscience

Department

Biology

Advisor

Constantine Bitsaktsis, Ph.D.

Committee Member

Daniel B. Nichols, Ph.D.

Committee Member

Gregory R. Wiedman, Ph.D.

Committee Member

Tinchun T. Chu, Ph.D.

Committee Member

Jessica Cottrell, Ph.D.

Keywords

gamma-delta (γδ) T cells; vaccine; memory cell formation

Abstract

Francisella tularensis is a highly infectious intracellular bacterium and the causative agent of tularemia, with pulmonary infection resulting in severe disease and high mortality if untreated. While protective immunity to F. tularensis has been largely attributed to CD4⁺ T cell–mediated IFN-γ responses, the contribution of γδ T cells to mucosal immunity and vaccine-induced protection remains poorly defined. The objective of this study was to characterize the role of γδ T cells during primary pulmonary infection with F. tularensis live vaccine strain (LVS) and following intranasal immunization with inactivated F. tularensis (iFt) prior to LVS challenge.

Using a murine intranasal infection model, we demonstrate that γδ T cells are rapidly recruited to the lung during primary LVS infection, appearing as early as Day 2 post-infection and preceding the accumulation of conventional αβ T cells. Cytokine profiling revealed that γδ T cells were predominantly IL-17–producing rather than IFN-γ–producing, with lung IL-17 levels correlating with increased frequencies of IL-17⁺ γδ T cells. In contrast, IFN-γ production was observed in the lung but was not primarily derived from γδ T cells.

Following iFt immunization and subsequent LVS challenge, immunized mice exhibited enhanced early IL-17 responses, including a significant increase in IL-17⁺ γδ T cells within the first 48 hours post-challenge. This early cytokine response was associated with the generation of both effector and central memory IL-17–producing γδ T cell populations, suggesting a memory-like function for these cells. Immunized mice also displayed reduced inflammatory cell infiltration at later time points, consistent with improved bacterial control and resolution of inflammation.

Collectively, this study provides the first comprehensive in vivo characterization of γδ T cell responses following intranasal iFt immunization and F. tularensis LVS challenge. Our findings identify IL-17–producing γδ T cells as early responders that bridge innate and adaptive immunity in the lung and support a previously underappreciated role for γδ T cell–mediated IL-17 responses in protective mucosal immunity against F. tularensis. These insights have important implications for the design of next-generation intranasal vaccines targeting intracellular respiratory pathogens.

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