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Unravelling the Complexity of T Cell Abnormalities in Common Variable Immunodeficiency¹

Antonello Giovannetti^2,3,*, Marina Pierdominici^2,, Francesca Mazzetta, Marco Marziali, Cristina Renzi, Anna Maria Mileo^¶, Marco De Felice, Barbara Mora^||, Antonella Esposito, Rossella Carello^#, Antonio Pizzuti^||, Marco G. Paggi^¶, Roberto Paganelli^**, Walter Malorni and Fernando Aiuti

^* Department of Clinical Medicine, Division of Allergy and Clinical Immunology, "La Sapienza" University, Rome, Italy; Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy; Interregional Center for Primary Immunodeficiencies, Department of Clinical Medicine, "La Sapienza" University, Rome, Italy; Epidemiology Unit, Istituto Dermopatico dell’Immacolata, Rome, Italy; ^¶ Department for the Development of Therapeutic Programs, Center for Experimental Research, Regina Elena Cancer Institute, Rome, Italy; ^|| Institute Casa Sollievo della Sofferena-Mendel, Rome, Italy; ^# Doctoral School of Research in Science of Immunotherapy, University of Rome "La Sapienza," Rome, Italy; ^** Department of Medicine and Sciences of Aging, "G. d’Annunzio" University, Chieti, Italy; and Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy

We investigated several phenotypic and functional parameters of T cell-mediated immunity in a large series of common variable immunodeficiency (CVID) patients. We demonstrated that the vast majority of CVID patients presented multiple T cell abnormalities intimately related among them, the severity of which was reflected in a parallel loss of CD4⁺ naive T cells. A strong correlation between the number of CD4⁺ naive T cells and clinical features was observed, supporting the subgrouping of patients according to their number of naive CD4⁺ T lymphocytes. A reduced thymic output and disrupted CD4⁺ and CD8⁺ TCR repertoires paralleled the contraction of CD4⁺ naive T cell pools. The evaluation of activation markers and cytokine production indicated a strong T cell activation that was significantly related to the increased levels of T cell turnover and apoptosis. Finally, discrete genetic profiles could be demonstrated in groups of patients showing extremely diverse T cell subset composition and function. Naive CD4⁺ T cell levels were significantly associated with the switched memory B cell-based classification, although the concordance between the respective subgroups did not exceed 58.8%. In conclusion, our data highlight the key role played by the T cell compartment in the pathogenesis of CVID, pointing to the need to consider this aspect for classification of this disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from University of Rome, Faculty of Medicine 2001–2004 and 2004–2006 for Primary Immunodeficiencies (to F.A.); Ministero dell’Università e della Ricerca Scientifica e Technologica, projects for Primary Immunodeficiencies, 2002–2003 (to F.A.); Istituto Superiore di Sanità, 2003–2005 (to F.A.); and Istituto Superiore di Sanità, 2003–2004, Grant C3AF (to M.P.).

² A.G. and M.P. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Antonello Giovannetti, Department of Clinical Medicine, Division of Clinical Immunology and Allergy, "La Sapienza" University, Viale dell’Università 37, 00185 Rome, Italy. E-mail address: antonello.giovannetti{at}uniroma1.it

⁴ Abbreviations used in this paper: CVID, common variable immunodeficiency; PI, propidium iodide; HCFC1, host cell factor 1; OR, odds ratio; CI, confidence interval; BV, -chain variable region; DC, dendritic cell.

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