Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ.

Louise M C Webb,Sigrid Fra‐Bido,Louise S Matheson,Nicolas Fazilleau,Silvia Innocentin,Noudjoud Attaf,Michelle A Linterman,Julien Novarino,Alexandre Bignon

doi:10.1111/acel.13295

Abstract

Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre‐Tfh) but no associated increase in germinal centre (GC)‐Tfh cells in aged mice, suggesting age‐driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch‐associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age‐associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age‐induced changes in T‐cell activation that affects the differentiation and ultimately the function of effector T cells.

Highlights

Ageing changes the composition and function of the immune system leading to greater susceptibility to infectious disease, reduced responses to vaccination and increased autoimmune manifestations in older individuals (Frasca et al, 2020; Goronzy & Weyand, 2019; Linterman, 2014; Nikolich-Zugich, 2018)
In order to look at the effect of age on early T follicular helper (Tfh) cell differentiation in vivo, we first sought to determine the characteristics of pre-Tfh cells to enable their identification following immunisation
This suggests that inhibition of Notch is required for RBPJ-driven pre-Tfh cell differentiation even though its expression and activation are unaffected by age

Summary

| INTRODUCTION

Lefebvre et al, 2012, 2016; Lorenzo et al, 2018; Szakal et al, 1990; Turner & Mabbott, 2017a, 2017b, 2017c; Yang et al, 1996; Zheng et al, 1997). We showed that older people have reduced numbers of Tfh cells in peripheral blood following influenza vaccination This was associated with a 5-fold reduction in production of vaccine-specific antibodies (Stebegg et al, 2020). This was seen following immunisation of older mice where reductions in GC size, titres of antigen-specific antibodies and numbers of GC-Tfh cells were evident (Stebegg et al, 2020) This suggested an altered GC-Tfh response in older individuals and that similar age-associated defects in the Tfh cell response are common between mice and humans. Whilst Notch activity is required, it is the age-driven increase in RBPJ expression that drives early Tfh cell differentiation

| RESULTS

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES