Dendritic cells from X-linked hyper-IgM patients present impaired responses toCandida albicansandParacoccidioides brasiliensis

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Abstract

Background

Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood.

Objective

To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens.

METHODS

DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response toCandida albicansandParacoccidioides brasiliensis.We also evaluated the ability ofC albicans–andP brasiliensis–pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (TH) 17 cells, and production of IFN-γ, TGF-β, IL-4, IL-5, and IL-17.

Results

Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally,in vitroincubation with soluble CD40L reversed the decreased IL-12 production and the skewed TH2 pattern response.

Conclusion

Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM.

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