Age promotes abortive T follicular helper cell differentiation by increasing Notch signalling.

Ageing profoundly changes our immune system. It is thought to be a driving factor in the morbidity and mortality associated with infectious disease in the elderly. T follicular helper (Tfh) cells are essential for the generation of long-lasting protective immunity yet we do not know how ageing effect the ability to generate these cells. In this study we examined the effect of age on Tfh-precursor formation in both humans. We found that age drives increased formation of these cells. Further investigation showed that T cells from older donors had altered T cell receptor signalling, increased expression of CXCR5. RNA-Sequencing analysis of cells during differentiation highlighted the Notch-associated transcription factor, RBPJ, as important. Importantly, genetic or chemical modulation of the Notch pathway was able to rescue the age-associated increase in CXCR5 expression and aberrant accumulation of Tfh-precursors. Despite accumulation of Tfh-precursors, increased Notch activation was not sufficient for further differentiation into full Germinal Center (GC)-Tfh cells. This cell-intrinsic failure to make GC-Tfh cells likely contributes to the defective GC responses in ageing. Overall design: RNA-Sequencing was performed on CD3/CD28 activated CD4+ T cells from 6 young donors and 6 older donors in the presence/absence of IL-12+TGFB. RNA was extracted on day 3 of activation.