Direct Binding of the pH-Regulated Protein 1 (Pra1) from Candida albicans Inhibits Cytokine Secretion by Mouse CD4+ T Cells.

Arne Bergfeld,Wen-Chao Song,Sandra Werner,Peter F Zipfel,Prasad Dasari,Axel A Brakhage,Niklas Beyersdorf,Thomas Hünig,Peter Hortschansky,Timothy R Hughes

doi:10.3389/fmicb.2017.00844

Abstract

Opportunistic infections with the saprophytic yeast Candida albicans are a major cause of morbidity in immunocompromised patients. While the interaction of cells and molecules of innate immunity with C. albicans has been studied to great depth, comparatively little is known about the modulation of adaptive immunity by C. albicans. In particular, direct interaction of proteins secreted by C. albicans with CD4+ T cells has not been studied in detail. In a first screening approach, we identified the pH-regulated antigen 1 (Pra1) as a molecule capable of directly binding to mouse CD4+ T cells in vitro. Binding of Pra1 to the T cell surface was enhanced by extracellular Zn2+ ions which Pra1 is known to scavenge from the host in order to supply the fungus with Zn2+. In vitro stimulation assays using highly purified mouse CD4+ T cells showed that Pra1 increased proliferation of CD4+ T cells in the presence of plate-bound anti-CD3 monoclonal antibody. In contrast, secretion of effector cytokines such as IFNγ and TNF by CD4+ T cells upon anti-CD3/ anti-CD28 mAb as well as cognate antigen stimulation was reduced in the presence of Pra1. By secreting Pra1 C. albicans, thus, directly modulates and partially controls CD4+ T cell responses as shown in our in vitro assays.

Highlights

Candida albicans is a commensal on human skin and mucosal surfaces
Zn2+ which is found in serum at a concentration of 10 μM (Feske et al, 2012) and beyond increased Pra1 binding to mouse CD4+ T cells (Figures 2A–C) with plateau levels of binding reached after 30 min of incubation (Figure 2D)
We describe the direct interaction of the secreted C. albicans protein Pra1 with mouse CD4+ T cells

Summary

Introduction

Candida albicans is a commensal on human skin and mucosal surfaces. In situations of immunosuppression, C. albicans may, become pathogenic. Prominent examples of C. albicans-induced pathologies are mucosal or skin candidiasis as well as C. albicans septicemia in ICU and/ or HIV/Aids patients (Klein et al, 1984; Sangeorzan et al, 1994; Leroy et al, 2009). In the latter cohorts, loss of CD4+ T cells is the hallmark of immunodeficiency. Loss of CD4+ T cells is the hallmark of immunodeficiency This highlights the importance of CD4+ T cells for controlling C. albicans infections in humans.

Methods

Results

Conclusion