Environmental and T Cell-Intrinsic Factors Limit the Expansion of Neonatal Follicular T Helper Cells but May Be Circumvented by Specific Adjuvants

Follicular Th (T-FH) cells have emerged as a new Th subset providing help to B cells and supporting their differentiation into long-lived plasma cells or memory B cells. Their differentiation had not yet been investigated following neonatal immunization, which elicits delayed and limited germinal center (GC) responses. We demonstrate that neonatal immunization induces CXCR5(high)PD-1(high) CD4(+) T-FH cells that exhibit T-FH features (including Batf, Bc16, c-Maf, ICOS, and IL-21 expression) and are able to migrate into the GCs. However, neonatal T-FH cells fail to expand and to acquire a full-blown GC T-FH phenotype, as reflected by a higher ratio of GC T-FH/non-GC CD4(+) T cells in immunized adults than neonates (3.8 x 10(-3) 2.2 x 10(-3), p = 0.01). Following the adoptive transfer of naive adult OT-II CD4(+) T cells, OT-II T-FH cells expand in the vaccine-draining lymph nodes of immunized adult but not infant recipients, whereas naive 2-wk-old CD4(+) OT-II cells failed to expand in adult hosts, reflecting the influence of both environmental and T cell intrinsic factors. Postponing immunization to later in life increases the number of T-FH cells in a stepwise manner, in direct correlation with the numbers of GC B cells and plasma cells elicited. Remarkably, adjuvantation with CpG oligonucleotides markedly increased GC T-FH and GC B cell neonatal responses, up to adult levels. To our knowledge, this is the first demonstration that the T-FH cell development limits early life GC responses and that adjuvants/delivery systems supporting T-FH differentiation may restore adultlike early life GC B cell responses. The Journal of Immunology, 2012, 189: 5764-5772.