Hao Fan, Zhong Zheng, Kaitlyn Oliphant, Jiacheng Li, Ryan Mack, Cheng‐Wei Ju, Brandon Trandai, Jiayi Tu, Freya Q. Zhang, Rukang Zhang, Zhicheng Xie, Chunzhao Yin, Chufan Cai, Megan S Kennedy, Tess McNeely, Candace M. Cham, Hardik Shah, Lei Dong, Rui Su, Camilia R. Martin, Brian T. Layden, Robert B. Hamanaka, Gökhan M. Mutlu, Eugene B. Chang, Jiwang Zhang, Hongbo Chi, Erika C. Claud, Chuan He, Jing Chen
How maternal nutrition influences neonatal immune development and imprinting through breastfeeding remains largely unclear. We report that maternal supplementation with trans-vaccenic acid (TVA), the predominant naturally occurring trans-fatty acid in human breast milk, promoted neonatal T cell development in mice. Neonates fed by mothers on a TVA-enriched diet showed an expanded naïve cluster of differentiation 4 (CD4 + ) T cell population and enhanced adaptive immunity against infection. TVA reprogrammed neonatal naïve CD4 + T cells through a G protein–coupled receptor–CCCTC-binding factor axis and promoted T helper cells (Th1)–skewing by cooperating with the transcription factor TBX21. Early-life exposure to maternal TVA via breastfeeding supported long-lasting antiviral immunity in adulthood. Our findings establish the multifaceted benefits of maternal nutrition and breastfeeding via TVA in promoting infant immune homeostasis and protective immunity.