RESUMEN
Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.
Asunto(s)
Centro Germinal/fisiología , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Células T Auxiliares Foliculares/fisiología , Linfocitos T Colaboradores-Inductores/fisiología , Adolescente , Traslado Adoptivo , Adulto , Anciano , Envejecimiento , Animales , Linfocitos B , Células de la Médula Ósea , Antígenos CD11/genética , Antígenos CD11/metabolismo , Quimera , Femenino , Humanos , Inmunidad Humoral , Memoria Inmunológica , Vacunas contra la Influenza/administración & dosificación , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/veterinaria , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/metabolismo , Vacunación , Adulto JovenRESUMEN
Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.
