Epigenetic reprogramming of CD4⁺ T cell fate by maternal and early-life obesity impairs vaccine responses in the offspring [Spatial Transcriptomics]

Despite the alarming global rise in maternal and childhood obesity, its impact on early-life adaptive immune responses to vaccination or infection remains largely undefined. Using a mouse model that mirrors the epidemiological link between maternal and childhood obesity, we demonstrate that exposure to a high-fat diet (HFD) during pregnancy or early postnatal life, but not in adulthood, profoundly reshapes the epigenetic and transcriptional landscape of early-life naïve CD4⁺ T cells, impairing their ability to differentiate into T follicular helper (Tfh) cells in response to both mRNA- and protein-based vaccines.

Consequently, germinal center (GC) reactions, the Tfh cell–drive process essential for establishing long-lived humoral immunity after vaccination or infection are markedly compromised by maternal and early-life diet-induced obesity. Mechanistically, we identify epigenetic repression of the ubiquitin-editing enzyme A20 (TNFAIP3), a key component of the Tfh transcriptional program, as the central driver of these defects.