An attractive strategy to improve efficacy of current Influenza A Virus (IAV) vaccines is to promote protective CD4 T cell responses. Antiviral CD4 T cell responses are predominantly classified as strong IFN-gamma producing T helper type 1 (Th1) cells. Yet, the role of IFN-gamma in protection against IAV is still unclear, suggesting absolute Th1 polarization may be expendable for effective IAV immunity. Here we test this hypothesis using models that restrict the deficiency of known transcriptional regulators of Th1 immunity in only CD4 T cells, avoiding indirect impact on other immune cell responses. We find the 'master regulator' of Th1 cells, the T-box transcription factor T-bet (Tbx21), to be dispensable for CD4 T cell-mediated protection from lethal IAV but important for maximizing the magnitude of effector responses by regulating cell trafficking to the lung. While donor Tbx21-/- responses gain Th17 characteristics, they still produce substantial IFN-gamma, suggesting their Th1 attributes may still be required for protection. Interestingly, Tbx21-/- cells expressed more Eomesodermin (Eomes), a paralog of T-bet, but Eomes-/- cells retain WT-like responses suggesting minor roles for Eomes in presence of T-bet. In contrast, Tbx21-/-Eomes-/- cells, completely lose their Th1 identity but remarkably exhibit stronger inflammation-induced Th17 attributes than Tbx21-/- cells. Strikingly, we find in vitro Th17-primed Tbx21-/-Eomes-/- effectors lose their plasticity to become Th1 but instead strengthen their Th17-ness in IAV infected mice but still protect. Finally, we observed that protection of previously primed Tbx21-/- and Tbx21-/-Eomes-/- mice from a lethal unrelated IAV strain required T cell mediated immunity. Our observations thus demonstrate novel roles for Eomes in broadening the scope of protective mechanisms against IAV. Furthermore, we decisively demonstrate protective roles for prototypical non-plastic Th17 responses in primary and secondary responses, thus increasing the scope of target mechanisms relevant for CD4 T-cell based vaccination strategies against viral pathogens.


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Graduation Date





McKinstry, Karl


Doctor of Philosophy (Ph.D.)


College of Medicine


Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences




CFE0008466; DP0024142





Release Date

May 2024

Length of Campus-only Access

3 years

Access Status

Doctoral Dissertation (Open Access)