CXCR5 + PD-1 ++ CD4 + T cells colonize infant intestines early in life and promote B cell maturation.

Gastrointestinal infections are a major cause for serious clinical complications in infants. The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5 + PD-1 ++ CD4 + T cells (T FH cells). We investigated the ontogeny of CXCR5 + PD-1 ++ CD4 + T cells in human intestines. While CXCR5 + PD-1 ++ CD4 + T cells were absent in fetal intestines, CXCR5 + PD-1 ++ CD4 + T cells increased after birth and were abundant in infant intestines, resulting in significant higher numbers compared to adults. These findings were supported by scRNAseq analyses, showing increased frequencies of CD4 + T cells with a T FH gene signature in infant intestines compared to blood. Co-cultures of autologous infant intestinal CXCR5 + PD-1 +/- CD4 + T cells with B cells further demonstrated that infant intestinal T FH cells were able to effectively promote class switching and antibody production by B cells. Taken together, we demonstrate that functional T FH cells are numerous in infant intestines, making them a promising target for oral pediatric vaccine strategies.