Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency

Giulia Milardi, Biagio Di Lorenzo, Jolanda Gerosa, Federica Barzaghi, Gigliola Di Matteo, Maryam Omrani, Tatiana Jofra, Ivan Merelli, Matteo Barcella, Matteo Filippini, Anastasia Conti, Francesca Ferrua, Francesco Pozzo Giuffrida, Francesca Dionisio, Patrizia Rovere-Querini, Sarah Marktel, Andrea Assanelli, Simona Piemontese, Immacolata Brigida, Matteo ZoccolilloEmilia Cirillo, Giuliana Giardino, Maria Giovanna Danieli, Fernando Specchia, Lucia Pacillo, Silvia Di Cesare, Carmela Giancotta, Francesca Romano, Alessandro Matarese, Alfredo Antonio Chetta, Matteo Trimarchi, Andrea Laurenzi, Maurizio De Pellegrin, Silvia Darin, Davide Montin, Maddalena Marinoni, Rosa Maria Dellepiane, Valeria Sordi, Vassilios Lougaris, Angelo Vacca, Raffaella Melzi, Rita Nano, Lucia Bongiovanni, Caterina Cancrini, Lorenzo Piemonti, Raffaella Di Micco, Maurilio Ponzoni, Alessandro Aiuti, Maria Pia Cicalese, Georgia Fousteri

Research output: Contribution to journalArticlepeer-review

Abstract

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.

Original languageEnglish
Pages (from-to)1171-1189
Number of pages19
JournalEuropean Journal of Immunology
Volume52
Issue number7
DOIs
Publication statusPublished - Jul 2022

Keywords

  • B cells
  • Common variable immunodeficiency
  • Immune aging
  • T follicular helper cells
  • T-cell exhaustion

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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