TH1 phenotype of T follicular helper cells indicates an IFNγ-associated immune dysregulation in CD21low CVID patients

Publication date: Available online 26 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Susanne Unger, Maximilian Seidl, Pauline van Schouwenburg, Mirzokhid Rakhmanov, Alla Bulashevska, Natalie Frede, Bodo Grimbacher, Jens Pfeiffer, Klaudia Schrenk, Luis Munoz, Leif Hanitsch, Ina Stumpf, Fabian Kaiser, Oliver Hausmann, Florian Kollert, Sigune Goldacker, Mirjam van der Burg, Baerbel Keller, Klaus Warnatz
BackgroundA subgroup of patients with Common Variable Immunodeficiency (CVID) suffers from immune dysregulation, manifesting as autoimmunity, lymphoproliferation and organ inflammation, and thereby increasing morbidity and mortality. Therefore, treatment of these complications demands a deeper comprehension of their etiology and pathophysiology.ObjectivesBased on the identification of an Interferon (IFN) signature in CVID patients with secondary complications and a skewed T follicular helper cell (TFH) differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients.MethodsWe quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of CVID patients by flow cytometry, analyzed their function and correlated all findings to the burden of immune dysregulation.ResultsCVID patients with immune dysregulation had a skewed memory CD4 T-cell differentiation towards a CXCR3^posCCR6^neg TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings we observed a higher IFNγ production in peripheral CD4 memory T cells and lymph node-derived TFH cells of CVID patients compared to healthy controls. Increased IFNγ production was accompanied by a poor GC output, an accumulation of T-bet^pos B cells in lymph nodes and T-bet^pos CD21^low B cells in peripheral blood of affected patients.ConclusionThe identification of an excessive IFNγ production by blood and lymph node-derived T cells of CVID patients with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21^low B cells may serve as a marker of this IFNγ-associated dysregulation.



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