Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo

Abstract

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. Abnormalities of CD4+CD25high forkhead box P3 (FoxP3)+ regulatory T cells (Treg) have been associated with autoimmune and inflammatory disorders, and we hypothesized that CVID might be characterized by Treg abnormalities. CD3+ cells from patients and controls were analysed for the expression of FoxP3 mRNA by real time reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells from CVID patients and controls were stained for Treg markers, analysed by flow cytometry and compared to clinical characteristics. The main findings were: (i) CVID patients had significantly decreased expression of FoxP3 mRNA and decreased proportions of CD4+CD25highFoxP3+ cells compared to controls; (ii) CVID patients with splenomegaly had even lower proportions of Treg compared to other patients and controls; (iii) serum levels of the inflammatory marker neopterin were correlated negatively with the proportions of Treg within the CVID population, while there was no significant association with bronchiectasis. We have demonstrated decreased proportions of Treg in CVID patients, particularly in those with signs of chronic inflammation. Decreased proportions of TReg are suggested to be pathogenetically important in autoimmunity, and our results suggest that TReg may have a similar role in CVID.

Fig. 1

Expression of forkhead box P3 (FoxP3) mRNA in T cells (a) and proportions of CD4⁺CD25^highFoxP3⁺ cells in the CD4⁺ cell population (b) among healthy controls and common variable immunodeficiency patients.

Fig. 2

CD4⁺CD25^high and CD4⁺CD25^highforkhead box P3 (FoxP3)⁺ cells in one representative healthy control (a, b, respectively) and in one representative common variable immunodeficiency (CVID) patient with splenomegaly (c, d, respectively) as measured by flow cytometry. Boxes (a, c) indicate cells in the CD25^high population. Quadrants (b, d) indicate CD25^highversus CD25^{low/intermediate} cells and FoxP3⁺versus FoxP3^– cells.

Fig. 3

Proportions of CD4⁺CD25^highforkhead box P3 (FoxP3)⁺ cells in the CD4⁺ cell population among healthy controls and common variable immunodeficiency (CVID) patients with and without splenomegaly (a). Correlation between proportions of CD4⁺CD25^highFoxP3⁺ cells and serum levels of neopterin in CVID patients (b).