Follicular helper T cell signature of replicative exhaustion, apoptosis and senescence in common variable immunodeficiency
Authors: Milardi Giulia , Lorenzo Biagio Di , Gerosa Jolanda , Barzaghi Federica , Matteo Gigliola Di , Omrani Maryam , Jofra Tatiana , Merelli Ivan , Barcella Matteo , Ferrua Francesca , Giuffrida Francesco Pozzo , 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 , Cesare Silvia Di , Giancotta Carmela , Romano Francesca , Matarese Alessandro , Chetta Alfredo Antonio , Trimarchi Matteo , Laurenzi Andrea , Pellegrin Maurizio De , Darin Silvia , Montin Davide , 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 , Ponzoni Maurilio , Aiuti Alessandro , Cicalese Maria Pia , Fousteri Georgia 
Published: June 2021

AbstractBackgroundCommon variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. A significant number of CVID patients are affected by various manifestations of immune dysregulation such as autoimmunity. Follicular T cells cells are thought to support the development of CVID by providing inappropriate signals to B cells during the germinal center (GC) response.ObjectivesWe determined the possible role of follicular helper (Tfh) and follicular regulatory T (Tfr) cells in patients with CVID by phenotypic, molecular, and functional studies.MethodsWe analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh cells in the peripheral blood of 27 CVID patients (11 pediatric and 16 adult) displaying autoimmunity as additional phenotype and compared them to 106 (39 pediatric and 67 adult) age-matched healthy controls. We applied Whole Exome Sequencing (WES) and Sanger sequencing to identify mutations that could account for the development of CVID and associate with Tfh alterations.ResultsA group of CVID patients (n=9) showed super-physiological frequency of Tfh1 cells and a prominent expression of PD-1 and ICOS, as well as a Tfh RNA signature consistent with highly active, but exhausted and apoptotic cells. Plasmatic CXCL13 levels were elevated in these patients and positively correlated with Tfh1 cell frequency, PD-1 levels, and an elevated frequency of CD21loCD38loautoreactive B cells. Monoallelic variants inRTEL1, a telomere length- and DNA repair-related gene, were ideintified in four patients belonging to this group. Lymphocytes with highly shortened telomeres, and a Tfh signature enriched in genes involved in telomere elongation and response to DNA damage were seen. Histopathological analysis of the spleen in one patient showed reduced amount and size of the GC that, unexpectedly, contained an increased number of Tfh cells.ConclusionThese data point toward a novel pathogenetic mechanism in a group of patients with CVID, whereby alterations in DNA repair and telomere elongation might be involved in GC B cells, and acquisition of a Th1, highly activated but exhausted and apoptotic phenotype by Tfh cells.