Dendritic Cells From X-Linked Hyper-IgM Patients Present Impaired Responses to Candida Albicans and Paracoccidioides Brasiliensis That Can Be Reversed by Exogenous Soluble CD40L

Abstract

S U N D A Y 457 Dendritic Cells From X-Linked Hyper-IgM Patients Present Impaired Responses to Candida Albicans and Paracoccidioides Brasiliensis That Can Be Reversed by Exogenous Soluble CD40L Otavio C. Marques, Christina Arslanian, Rodrigo N. Ramos, Mariana M. Marques, Lena F. Schimke, Paulo V. S. Pereira, Sonia Jancar, Janaira F. S. Ferreira, Cristina W. Weber, Gisele Kuntze, Nelson Augusto Rosario-Filho, Beatriz C. Carvalho, Patr icia C. BergamiSantos, Mary J. Hackett, Hans D. Ochs, Troy R. Torgerson, Jos e Alexandre M. Barbuto, Antonio Condino-Neto; Institute of Biomedical Sciences, Department of Immunology, University of S~ao Paulo, Sao Paulo, Brazil, S~ao Paulo, Brazil, University of S~ao Paulo, Institute of Biomedical Sciences, Department of Immunology, University of S~ao Paulo, Sao Paulo, Brazil, Albert Sabin Hospital, Pediatric and Immunology Clinic, RS, Pequeno Principe Hospital, Federal University of Paran a, Federal University of S~ao Paulo, University of Washington, *Contributed Equally. RATIONALE: Patients with X-linked hyper-IgM syndrome (XHIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood. 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 to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans– and P brasiliensis–pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (TH) 17 cells, and production of IFN-g, TGF-b, 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-g production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the DCs phenotype, the decreased IL-12 production and the skewed TH2 pattern response. CONCLUSIONS: 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.