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 3

T-bet–deficient immunity is altered during pregnancy and fails to protect the maternal-fetal unit from the adverse outcomes of IAV.

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T-bet–deficient immunity is altered during pregnancy and fails to protec...
C57BL/6J WT and T-bet–deficient (KO) timed-pregnant gravid mice were infected with 0.5 LD50 PR8 at the transition between the first and second trimester of pregnancy and (A) survival and morbidity, and (B) lung viral titers on 7 dpi were monitored (representative of 2 independent experiments with n = 5–6 per group per experiment). Parturition is marked with an arrow. In separate experiments, 2 × 106 naive congenic T-bet–deficient OT-II CD4+ TcR Tg cells were transferred to nongravid (NG) or timed-pregnant gravid (G) WT C57BL/6J recipients that were subsequently infected as described above with 0.2 LD50 PR8-OVAII (C). On 7 dpi, donor responses in the spleen, dLN, and lung were characterized by flow cytometry and ICCS (n = 4 per group, representative of 2 separate experiments). Expression of (D) T-bet, and (E) enumeration of donor cells. Control histograms in (D) are WT host T cells. (F) GATA-3hi expression by donor cells and (G) frequency of GATA-3hi expressing donor cells in all organs. Representative donor cell ICCS staining and enumeration of dual IFN-γ and IL-2 and IL-4– and IL-5–and IL-13–producing cells in all organs (H–K). The Log Rank test was used in A, and Students t test for pairwise comparisons in B, E, G, I, and K.