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

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          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.

          Abstract

          Ageing alters TCR signalling which drives expression of the Notch‐associated transcription factor, RBPJ. This results in enhanced differentiation into T follicular helper cell precursors.

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          Most cited references 74

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          The canonical Notch signaling pathway: unfolding the activation mechanism.

          Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.
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            Molecular and cellular insights into T cell exhaustion.

            In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.
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              Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements.

              We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating these transgenic mice utilized heterologous regulatory elements to drive the expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR. Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from the thymus in these mice, although the transgenes did modify endogenous TCR expression. However, subsequent modification of the approach which enabled expression of the TCR beta-chain under the control of its natural regulatory elements generated mice whose peripheral T cells expressed the transgenic TCR and were capable of antigen-dependent proliferation. These results show that successful generation of MHC class II-restricted, OVA-specific alpha beta TCR transgenic mice was dependent upon combining cDNA- and genomic DNA-based constructs for expression of the respective alpha- and beta-chains of the TCR.
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                Author and article information

                Contributors
                michelle.linterman@babraham.ac.uk
                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                02 January 2021
                January 2021
                : 20
                : 1 ( doiID: 10.1111/acel.v20.1 )
                Affiliations
                [ 1 ] Laboratory of Lymphocyte Signalling and Development Babraham Institute Babraham UK
                [ 2 ] Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) Inserm U1291University of Toulouse Toulouse, F CNRS U5282 France
                Author notes
                [* ] Correspondence

                Michelle A. Linterman, Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham, UK.

                Email: michelle.linterman@ 123456babraham.ac.uk

                Article
                ACEL13295
                10.1111/acel.13295
                7811847
                33387451
                © 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 7, Tables: 1, Pages: 19, Words: 11955
                Product
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council , open-funder-registry 10.13039/501100000268;
                Award ID: BBS/E/B/000C0427
                Award ID: BBS/E/B/000C0428
                Funded by: H2020 European Research Council , open-funder-registry 10.13039/100010663;
                Award ID: 637801‐TWILIGHT
                Funded by: Babraham Institute , open-funder-registry 10.13039/100012067;
                Funded by: Region Occitanie/Pyrénées‐Méditerranée
                Award ID: 1901175
                Funded by: European Regional Development Fund , open-funder-registry 10.13039/501100008530;
                Award ID: MP0022856
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                January 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:17.01.2021

                Cell biology

                age, cxcr5, notch, rbpj, t follicular helper cells

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