Defective IL-4 signaling in T cells defines severe common variable immunodeficiency

J Autoimmun. 2017 Jul;81:110-119. doi: 10.1016/j.jaut.2017.04.004. Epub 2017 May 3.


Common variable immunodeficiency (CVID) is defined by hypogammaglobulinemia and B-cell dysfunction, with significant clinical and immunological heterogeneity. Severe non-infectious complications, such as autoimmunity, granulomatous disease and splenomegaly, constitute a major cause of morbidity in CVID patients. T cells are generally regarded important for development of these clinical features. However, while T-cell abnormalities have been found in CVID patients, functional characteristics of T cells corresponding to well-defined clinical subtypes have not been identified. As common γ-chain cytokines play important roles in survival and differentiation of T cells, characterization of their signaling pathways could reveal functional differences of clinical relevance. We characterized CVID T cells functionally by studies of cytokine-induced signaling, and correlated the findings to defined clinical subtypes. Peripheral blood T cells from 29 CVID patients and 19 healthy donors were analyzed for i) phenotype, ii) cytokine-induced (interleukin (IL)-2, IL-4, IL-7 and IL-21) phosphorylation of signal transducer and activator of transcription (STAT) 3, STAT5 and STAT6, and iii) T-helper (Th)1/Th2 polarization. Expression of IL-4 receptor and downstream signaling molecules was measured. A subgroup of CVID patients (n = 7) was identified by impaired IL-4-induced p-STAT6 in naive and memory CD4 and CD8 T cells. This corresponded to patients with the largest accumulation of severe (non-infectious) complications. The signaling defect persisted over years and was not due to constitutively activated p-STAT6. The CD4 T cells were strongly Th1-skewed, but IL-4 signaling was impaired independently of Th status. However, IL-4Rα and Janus kinase (JAK) 1 mRNA levels were significantly lower than in normal donors, providing a likely mechanism for the defective IL-4-induced p-STAT6 and Th1-bias. In conclusion, we identified a subgroup of CVID patients with defective IL-4 signaling in T cells, with severe clinical features of inflammation and autoimmunity.

Keywords: Autoimmunity; CVID; Hypogammaglobulinemia; IL-4 signaling; IL-4Rα; Phospho-flow cytometry; T cell; Th1.

MeSH terms

  • Adult
  • Biomarkers
  • Common Variable Immunodeficiency / complications
  • Common Variable Immunodeficiency / diagnosis
  • Common Variable Immunodeficiency / immunology*
  • Common Variable Immunodeficiency / metabolism*
  • Female
  • Gene Expression
  • Humans
  • Immunophenotyping
  • Interleukin-4 / metabolism*
  • Janus Kinase 1 / metabolism
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism
  • STAT6 Transcription Factor / metabolism
  • Severity of Illness Index
  • Signal Transduction*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th2 Cells / immunology
  • Th2 Cells / metabolism


  • Biomarkers
  • Programmed Cell Death 1 Receptor
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Interleukin-4
  • Janus Kinase 1