Immunomodulation in human dendritic cells leads to induction of interferon-gamma production by Leishmania donovani derived KMP-11 antigen via activation of NF-κ B in Indian Kala-Azar patients

Abstract

Dendritic cells (DCs) and macrophages (M Φ s) are well-known antigen presenting cells with an ability to produce IL-12 which indicates that they have potential of directing acquired immunity toward a Th1-biased response. The aim of this study was to examine the effect of Leishmania specific KMP-11 antigen through comparison of immune responses after presentation by DCs and M Φ s to T cells in Indian patients with VL. Patients with DCS and M Φ s were directed against a purified Leishmania donovani antigen (KMP-11) and phytohaemagglutinin (PHA). The cytokines (IL-12, IL-10, and TGF- β) producing abilities of the DCs and M Φ s against these antigens were determined by flow cytometry. The transcription factor (NF- κ B) and T-cell cytokine support (IFN- γ, IL-10), which could be significant in effector immune function, were also determined. Severe hindrance in the immune protection due to Leishmania parasites, as revealed by decreased expression of IL-12 and upregulation of IL-10 and TGF- β expression in the M Φ s compared to DCs, occurred in VL patients. The production of IL-12 in response to L. donovani KMP-11 antigen was increased in DCs which was reduced in M Φ s of VL patients. In contrast, the presentation of KMP-11 antigen by DCs to T-lymphocytes in VL patients significantly increased the IFN- γ produced by these immune cells, whereas the levels of IL-10 were significantly elevated after presentation of KMP-11antigen by M Φ s. The VL patients were observed with severely dysfunctional M Φ s in terms of NF- κ B activity that could be recovered only after stimulation of DCs with L. donovani KMP-11 antigen. Immunologically the better competitiveness of KMP-11 antigen through a dendritic cell delivery system may be used to revert T-cell anergy, and control strategy can be designed accordingly against kala-azar. © 2014 Rajesh Chaudhary et al.