Impaired selective cytokine production by CD4 + T cells in Common Variable Immunodeficiency associated with the absence of memory B cells Laura Berrón-Ruiz a , Gabriela López-Herrera a , Alexander Vargas-Hernández b , Leopoldo Santos-Argumedo b , Constantino López-Macías c , Armando Isibasi c , Nora Hilda Segura-Méndez d , Laura Bonifaz c, ⁎ a Unidad de Investigación en Inmunodeficiencias, Instituto Nacional de Pediatría SSa, Av. Insurgentes Sur # 3700-C, Colonia Insurgentes Cuicuilco, México, D.F, México b Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados, IPN,, Av. Instituto Politécnico Nacional # 2508, Colonia Zacatenco, 07360 México, D.F, México c Unidad de Investigación Médica en Inmunoquímica Hospital de Especialidades Centro Médico Nacional (CMN) Siglo XXI. Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtémoc 330, Col. Doctores, C.P. 06720 México, D.F, México d Servicio de Alergia e Inmunología Clínica, Hospital de Especialidades CMN, Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, C.P. 06720 México, D.F, México abstract article info Article history: Received 3 December 2015 Received in revised form 18 March 2016 Accepted with revision 28 March 2016 Available online xxxx Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by B cell dysfunction and decreased serum immunoglobulin. CVID patients are classified by the absence or presence of memory B cells. In addition, T cell defects have been demonstrated in only a proportion of CVID patients. The aim of this study was to evaluate the function of CD4 + T cells from CVID patients and its association with memory B cells. Patients were classified according to their Freiburg groups: group Ia and Ib, with decreased switched memory B cells (b 0.4 of PBL), and group II, with normal B cell subsets. Their T cell function was evaluated after stimulation. We observed normal and even increased CD4 + T cell proliferation in group Ia (p = 0.0277). The proliferation positively correlated with the clinical severity score (r = 0.4796). We observed lower levels of IL-17A and IL-10 in group Ia (p = 0.0177, 0.0109) and Ib (p = 0.0009, 0.0084) patients. Group Ib patients also had low levels of IL-13 and IL-9 (p = 0.0169, 0.010). Group II patients had similar cytokine production to that of the controls. BAFFR expression was reduced in groups Ia (p = 0.0001) and Ib (p = 0.0002) and showed an inverse correlation with the severity score (p = 0.0262; r = 0.5371). ICOS expression was reduced in group Ia (p = 0.0364), and PD-1 was increased in group Ib (p = 0.0432) patients. This study shows a selective impairment in cytokine production in group Ia patients, which was more extensive than in group Ib patients. The impairment was associated with BAFFR expression in B cells, with ICOS and PD-1 in T cells and, remarkably, with the absence of memory B cells and with the disease severity. Our results suggest that the evaluation of cytokine expression by T cells in combination with the study of B cell memory could be important for understand the pathogenesis of CVID patients. © 2016 Elsevier Inc. All rights reserved. Keywords: Common variable immunodeficiency Memory B cells T helper cells Cytokine Activation Co-stimulation 1. Introduction Common Variable Immunodeficiency (CVID) is a primary immunode- ficiency characterized by B cell dysfunction, decreased serum immuno- globulin and failure to produce antigen-specific antibodies in response to vaccinations or infections [1]. Recurrent infections, autoimmune diseases, other forms of immune dysregulation such as granulomatous inflammation and malignancies are the most common manifestations in these patients, and regular immunoglobulin replacement is usually necessary [2,3]. In contrast to most other primary immunodeficiencies, more that 90% of documented CVID patients are lacking a definite molecular genetic diagnosis or other causal explanation for their disease. In a minority of patients with CVID, distinct molecular genetic defects have been identified [4]. These genes associated with a CVID phenotype are the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) [5], inducible costimulator (ICOS) [6], CD19 [7], B cell activating factor receptor (BAFFR) [8], CD81 [9], CD21 [10], CD20 [11], lipopolysaccharide responsive beige-like anchor protein (LRBA) [12]. In the majority of CVID patients, there is a failure of B cell differentiation that alters the peripheral blood B cell subsets; in 75% of cases, there is a loss of class-switched memory B cells [13]. Current classifications, such as the Freiburg [14] and Paris [15] schemes, rely upon such changes in the B cell subsets and their association with differ- ent clinical manifestations. B cells receive helper function from T cells either through direct cell-cell interaction or through the production of cytokines that interact Clinical Immunology xxx (2016) xxx–xxx Abbreviations: CVID, Common Variable Immunodeficiency; PBMCs, Peripheral blood mononuclear cells; PMA, Phorbol 12-myristrate 13-acetate; SEB, Staphylococcal enterotoxin B; MFI, mean fluorescence intensity; ICOS, Inducible coestimulator; BAFFR, B cell activating factor receptor; CTLA-4, Cytotoxic T lymphocyte antigen-4; PD-1, Programmed death; PDL-1, Programmed death ligand. ⁎ Corresponding author. E-mail address: labonifaz@yahoo.com (L. Bonifaz). YCLIM-07635; No. of pages: 8; 4C: http://dx.doi.org/10.1016/j.clim.2016.03.013 1521-6616/© 2016 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Clinical Immunology journal homepage: www.elsevier.com/locate/yclim Please cite this article as: L. Berrón-Ruiz, et al., Clin. Immunol. (2016), http://dx.doi.org/10.1016/j.clim.2016.03.013