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 1

Naive and memory CD4+ T cell responses against IAV are unaltered during pregnancy.

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Naive and memory CD4+ T cell responses against IAV are unaltered during ...
Congenic HNT CD4+ TcR Tg naive or memory CD4+ T cells, 3 × 106, were adoptively transferred to unprimed nongravid or timed-pregnant gravid BALB/c female recipients subsequently infected with 0.5 LD50 PR8. (A) Timeline showing the trimester and embryonic day (e) gravid mice were infected and (B) morbidity following infection. (C) Lung viral titers evaluated on 4 days post infection (dpi) (summation of 2 separate experiments with n = 4 per group). On 7 dpi, donor responses in spleen, draining lymph nodes (dLN), and lung were characterized by flow cytometry and ICCS. Representative staining is shown in D and E. Enumeration of donor cells and dual IFN-γ and IL-2 cytokine production for naive and memory cells (F–I). Representative T-bet, EOMES, and GATA-3 expression and corresponding MFI for naive (J and L) and memory (K and M) derived donor cells in the lung 7 dpi (n = 3–4 per group, representative of 2 separate experiments). Staining controls in (J and K) are naive CD4+ T cells. Ordinary 1-way ANOVA with Tukey’s multiple comparison post test was used in A and Students t test in F–M.