The TH1 phenotype of follicular helper T cells indicates an IFN-γ-associated immune dysregulation in patients with CD21low common variable immunodeficiency

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

doi:10.1016/j.jaci.2017.04.041

The T_H1 phenotype of follicular helper T cells indicates an IFN-γ-associated immune dysregulation in patients with CD21low common variable immunodeficiency

J Allergy Clin Immunol. 2018 Feb;141(2):730-740. doi: 10.1016/j.jaci.2017.04.041. Epub 2017 May 26.

Authors

Susanne Unger¹, Maximilian Seidl², Pauline van Schouwenburg³, Mirzokhid Rakhmanov⁴, Alla Bulashevska⁵, Natalie Frede⁵, Bodo Grimbacher⁵, Jens Pfeiffer⁶, Klaudia Schrenk², Luis Munoz⁷, Leif Hanitsch⁸, Ina Stumpf⁵, Fabian Kaiser⁹, Oliver Hausmann¹⁰, Florian Kollert¹¹, Sigune Goldacker⁵, Mirjam van der Burg³, Baerbel Keller⁵, Klaus Warnatz¹²

Affiliations

¹ Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
² Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute for Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany.
³ Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴ Center for Human Genetics and Laboratory Diagnostics (AHC), Martinsried, Germany.
⁵ Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁶ Department of Otorhinolaryngology-Head and Neck Surgery, University of Freiburg, Freiburg, Germany.
⁷ Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁸ Institute of Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
⁹ Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Löwenpraxis and Klinik St Anna, Luzern, Switzerland.
¹¹ Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany.
¹² Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: [email protected].

PMID: 28554560
DOI: 10.1016/j.jaci.2017.04.041

Abstract

Background: A subgroup of patients with common variable immunodeficiency (CVID) experience 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 cause and pathophysiology.

Objectives: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell 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.

Methods: We quantified T_H1/T_H2/T_H17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation.

Results: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3⁺CCR6^- T_H1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)⁺ B cells in lymph nodes, and an accumulation of T-bet⁺CD21^low B cells in peripheral blood of affected patients.

Conclusion: Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21^low B cells might serve as a marker of this IFN-γ-associated dysregulation.

Keywords: CD21(low) B cells; Follicular helper T cells; IFN-γ; T-bet; common variable immunodeficiency; germinal center.

Publication types

Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Common Variable Immunodeficiency / blood
Common Variable Immunodeficiency / immunology*
Common Variable Immunodeficiency / pathology
Female
Humans
Immunologic Memory*
Interferon-gamma / blood
Interferon-gamma / immunology*
Lymphocyte Count
Male
Middle Aged
Receptors, Complement 3d / blood
Receptors, Complement 3d / immunology*
T-Box Domain Proteins / blood
T-Box Domain Proteins / immunology
Th1 Cells / immunology*
Th1 Cells / metabolism
Th1 Cells / pathology

Substances

IFNG protein, human
Receptors, Complement 3d
T-Box Domain Proteins
T-box transcription factor TBX21
Interferon-gamma