title: Environmental and T cell-intrinsic factors limit the expansion of neonatal follicular T helper cells but may be circumvented by specific adjuvants.
abstract: 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, Bcl6, 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 × 10(-3) versus 2.2 × 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.
authors.affiliation: Department of Pathology-Immunology, World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, University of Geneva, CH-1211 Geneva 4, Switzerland.
authors.forename: Béatris
authors.initials: B
authors.lastname: Mastelic
authors.forename: Arun T
authors.initials: AT
authors.lastname: Kamath
authors.forename: Paola
authors.initials: P
authors.lastname: Fontannaz
authors.forename: Chantal
authors.initials: C
authors.lastname: Tougne
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Rochat
authors.forename: Elodie
authors.initials: E
authors.lastname: Belnoue
authors.forename: Christophe
authors.initials: C
authors.lastname: Combescure
authors.forename: Floriane
authors.initials: F
authors.lastname: Auderset
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Lambert
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tacchini-Cottier
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology*; D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D060833:Cellular Microenvironment / Q000276:immunology*; D016922:Cellular Senescence / Q000276:immunology; D018899:CpG Islands / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology* / Q000637:transplantation; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D013745:Tetanus Toxoid