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

Abstract

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., <i>CXCR5, IL-21, BCL6, TBK1, STAT4, ASCL2</i>, and <i>c-MAF</i>) 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.