Neonatal T Follicular Helper Cells Are Lodged in a Pre-T Follicular Helper Stage Favoring Innate Over Adaptive Germinal Center Responses

T follicular helper (T(fh)) cells have emerged as a critical limiting factor for controlling the magnitude of neonatal germinal center (GC) reactions and primary vaccine antibody responses. We compared the functional attributes of neonatal and adult T(fh) cells at the transcriptomic level and demonstrated that the T(fh) cell program is well-initiated in neonates although the T(fh) gene-expression pattern (i.e., CXCR5, IL-21, BCL6, TBK1, STAT4, ASCL2, and c-MAF) is largely underrepresented as compared to adult T(fh) cells. Importantly, we identified a TH2-bias of neonatal T(fh) cells, with preferential differentiation toward short-lived pre-T(fh) effector cells. Remarkably, adjuvantation with CpG-ODNs redirect neonatal pre-T(fh) cells toward committed GC-T(fh) cells, as illustrated by increased expression of T(fh) signature genes and reduced expression of TH2-related genes.