Dynamic regulation of TFH selection during the germinal centre reaction

• Published in: Nature (London) Vol. 591; no. 7850; pp. 458 - 463
• Main Authors: Merkenschlager, Julia, Finkin, Shlomo, Ramos, Victor, Kraft, Julian, Cipolla, Melissa, Nowosad, Carla R., Hartweger, Harald, Zhang, Wenzhu, Olinares, Paul Dominic B., Gazumyan, Anna, Oliveira, Thiago Y., Chait, Brian T., Nussenzweig, Michel C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2021; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/31; 14; 14/34; 14/63; 42; 42/35; 45/91; 59; 631/250/1619/40; 631/250/1619/554; Affinity; Antibodies; Antigens; Cell cycle; Cell division; Cell growth; Contraction; Coordination compounds; Cytokines; Gene expression; Germinal centers; Helper cells; Histocompatibility; Humanities and Social Sciences; Ligands; Lymphocytes; Lymphocytes B; Lymphocytes T; Microenvironments; multidisciplinary; Peptides; Receptors; Science; Science (multidisciplinary); Somatic hypermutation; T cell receptors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03187-x

The germinal centre is a dynamic microenvironment in which B cells that express high-affinity antibody variants produced by somatic hypermutation are selected for clonal expansion by limiting the numbers of T follicular helper cells 1 , 2 . Although much is known about the mechanisms that control the selection of B cells in the germinal centre, far less is understood about the clonal behaviour of the T follicular helper cells that help to regulate this process. Here we report on the dynamic behaviour of T follicular helper cell clones during the germinal centre reaction. We find that, similar to germinal centre B cells, T follicular helper cells undergo antigen-dependent selection throughout the germinal centre reaction that results in differential proliferative expansion and contraction. Increasing the amount of antigen presented in the germinal centre leads to increased division of T follicular helper cells. Competition between T follicular helper cell clones is mediated by the affinity of T cell receptors for peptide–major-histocompatibility-complex ligands. T cells that preferentially expand in the germinal centre show increased expression of genes downstream of the T cell receptor, such as those required for metabolic reprogramming, cell division and cytokine production. These dynamic changes lead to marked remodelling of the functional T follicular helper cell repertoire during the germinal centre reaction. T follicular helper cells undergo antigen-dependent selection in germinal centres, with higher-affinity T cell receptors supporting stronger proliferation leading to their clonal dominance.