Effects of glycodelin on CCR6⁺ cell subpopulations of Th17-polarized helper T cells

Abstract

Glycodelins, the glycosylated proteins of reproductive tract are characterized by immunomodulatory functions, are of interest because of their role in the development of immune tolerance. Interleukin-17-producing T helpers (Th17) bearing the surface marker CCR6, are a heterogeneous cell population with increased plasticity and functional dichotomy. On the one hand, these cells support antimicrobial and antifungal immunity and microbiota composition; on the other hand, they are involved in the pathogenesis of autoimmune diseases, graft rejection, and pregnancy complications. Despite the scientific interest in glycodelin as an immunomodulator, its direct effects on pro-inflammatory Th17 have not been studied. Therefore, the aim of our work was to investigate the effect of recombinant human glycodelin on Th17 polarization of naïve human T helper cells cells by assessing surface expression of CCR6, CCR4, and CXCR3 molecules. Naïve T helper cells were polarized for 7 days in vitro to Th17 cells with a TCR activator and cytokines for 7 days, supplemented with glycodelin at concentrations appropriate for the 1st and 2nd trimesters of pregnancy. The percentages of CD4+CCR6+ cell population (Th17 cells), and their CCR4+CXCR3-(Th17/Th22) and CCR4-CXC3+ subpopulations (Th17.1) was then determined. Moreover, the levels of IL-17, IL-2, and other cytokines/chemokines were determined in the culture supernatants of Th17-polarized T helper cells. Treatment with recombinant glycodelin at concentrations equivalent to those in pregnancy (0.2, 2, and 10 μg/mL) did not alter the percentage of CD4+CCR6+ cells in culture, or their IL-17 production. However, at a concentration of 10 μg/mL, it caused a decrease in Th17.1 (CCR6+CCR4-CXCR3+) percentage in the T helper culture, and increased the production of IL-2. In addition, glycodelin was found to have selective pro-apoptotic activity against Th17.1 if applied at 2 μg/mL. Given the known involvement of these cells in pathological processes, the observed effect of glycodelin could be of interest from a biopharmaceutical perspective. However, the mechanism of the revealed selective effects of this pregnancy protein needs further investigation.

Keywords

• glycodelin
• il-17
• th17
• ccr6⁺ t helpers
• pp14
• paep