Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice
Valeria Flores Malavet, … , K. Kai McKinstry, Tara M. Strutt
Valeria Flores Malavet, … , K. Kai McKinstry, Tara M. Strutt
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(1):e179230. https://doi.org/10.1172/JCI179230.
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Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice

Abstract

The risk of severe outcomes of influenza increases during pregnancy. Whether vaccine-induced T cell memory–primed prepregnancy retains the ability to mediate protection during pregnancy, when systemic levels of several hormones with putative immunomodulatory functions are increased, is unknown. Here, using murine adoptive transfer systems and a translationally relevant model of cold-adapted live-attenuated influenza A virus vaccination, we show that preexisting virus-specific memory T cell responses are largely unaltered and highly protective against heterotypic viral challenges during pregnancy. Expression of the transcription factor T-bet, which is upregulated in antiviral T cells responding in pregnant mice, is critical in preventing hormone-associated gain of detrimental T helper type 2 (TH2) attributes reported in other settings. Beyond antiviral effects, preexisting vaccine-primed T cell immunity prevents metabolic dysfunction in gravid dams and adverse neonatal outcomes often associated with maternal influenza infection. These results demonstrate robust protection of the maternal-fetal unit from severe consequences of respiratory virus infection by preexisting T cell immunity.

Authors

Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C. Arvelo, Aaron J. Beaird, Siva N. Annamalai, Lauren A. Kimball, K. Kai McKinstry, Tara M. Strutt

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Figure 2

TH1 effector IFN-γ production is unaltered by pregnancy levels of estradiol.

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TH1 effector IFN-γ production is unaltered by pregnancy levels of estrad...
Naive HNT CD4+ T cells were cultured in triplicate for 4 days with APC and peptide under TH1- or TH2-polarizing conditions. Media was supplemented with 17-β estradiol (E2), progesterone (P4), 17β-estradiol plus progesterone, or vehicle control (V) at concentrations comparable to those found systemically during the 1st (0.0176 μM E2 and 0.096 μM P4), 2nd (0.0353 μM E2 and 0.297 μM P4), and 3rd (0.0053 μM E2 and 0.382 μM P4) trimesters of pregnancy or administered pharmaceutically (Ph) (1 μM of E2 and P4). T-bet, EOMES, and GATA-3 transcription factor expression (A–C) ratio of TH1 IFN-γ (top row) and TH2 IL-4 (bottom row) cytokine secretion following culture with pregnancy hormones versus vehicle supplemented media. (D) MFI and representative histograms of Prohibitin-2 expression by TH1 and TH2 effectors cultured with and without supplemental 17-β estradiol. Naive (n) cell expression of Prohibitin-2 is shown as dashed line in graphs and nControl histograms. (E and F). Expression of estrogen receptor α (ERα) visualized with indirect surface, intracellular, and nuclear staining of polarized cells. Fluorescent-conjugated secondary Ab only control (2°Ab) histograms are indicated in E. Data representative of 3 replicate experiments. Students t- tests were used for pairwise comparisons in A and F, and ordinary 1-way ANOVA with Dunnett’s multiple comparison post test used in C and D.