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.
Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency / Milardi, Giulia; Di Lorenzo, Biagio; Gerosa, Jolanda; Barzaghi, Federica; Di Matteo, Gigliola; Omrani, Maryam; Jofra, Tatiana; Merelli, Ivan; Barcella, Matteo; Filippini, Matteo; Conti, Anastasia; Ferrua, Francesca; Pozzo Giuffrida, Francesco; Dionisio, Francesca; Rovere-Querini, Patrizia; Marktel, Sarah; Assanelli, Andrea; Piemontese, Simona; Brigida, Immacolata; Zoccolillo, Matteo; Cirillo, Emilia; Giardino, Giuliana; Danieli, Maria Giovanna; Specchia, Fernando; Pacillo, Lucia; Di Cesare, Silvia; Giancotta, Carmela; Romano, Francesca; Matarese, Alessandro; Chetta, Alfredo Antonio; Trimarchi, Matteo; Laurenzi, Andrea; De Pellegrin, Maurizio; Darin, Silvia; Montin, Davide; Marinoni, Maddalena; Dellepiane, Rosa Maria; Sordi, Valeria; Lougaris, Vassilios; Vacca, Angelo; Melzi, Raffaella; Nano, Rita; Azzari, Chiara; Bongiovanni, Lucia; Pignata, Claudio; Cancrini, Caterina; Plebani, Alessandro; Piemonti, Lorenzo; Petrovas, Constantinos; Di Micco, Raffaella; Ponzoni, Maurilio; Aiuti, Alessandro; Cicalese, Maria Pia; Fousteri, Georgia. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 1521-4141. - 52:7(2022), pp. 1171-1189. [10.1002/eji.202149480]