Defective IL-4 signaling in T cells defines severe common variable immunodeficiency. (July 2017)

• Record Type: Journal Article
• Authors: Taraldsrud, Eli; Fevang, Børre; Jørgensen, Silje F.; Moltu, Kristine; Hilden, Vera; Taskén, Kjetil; Aukrust, Pål; Myklebust, June H.; Olweus, Johanna
• Is Part Of: Journal of autoimmunity. Volume 81(2017)
• Page Start: 110
• Page End: 119
• Publication Date: 2017-07
• Subjects: Autoimmunity -- CVID -- IL-4Rα -- Th1 -- T cell -- Phospho-flow cytometry -- IL-4 signaling -- Hypogammaglobulinemia; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.04.004
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: 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. Highlights: A subset of CVID patients show persistently impaired IL-4-induced p-STAT6 in naïve and memory CD4 and CD8 T cells. The expression of IL-4Rα and JAK1 is low in T cells with defective IL-4 signaling. These features characterize CVID patients with the most severe form of the disease. These patients have strongly Th1-skewed CD4 T cells, but impaired IL-4-induced p-STAT6 is independent of Th status.