Abstract
The level of CD40 expression on dendritic cells (DCs) plays a decisive role in disease protection during Leishmania donovani (LD) infection. However, current understanding of the molecular regulation of CD40 expression remains elusive. Using molecular, cellular and functional approaches, we identified a role for Runx1 and Runx3 transcription factors in the regulation of CD40 expression in DCs. In response to lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα) or antileishmanial drug sodium antimony gluconate (SAG), both Runx1 and Runx3 translocated to the nucleus, bound to the CD40 promoter and upregulated CD40 expression on DCs. These activities of Runx proteins were mediated by the upstream phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Notably, LD infection attenuated LPS- or TNFα-induced CD40 expression in DCs by inhibiting PI3K-Akt-Runx axis via protein tyrosine phosphatase SHP-1. In contrast, CD40 expression induced by SAG was unaffected by LD infection, as SAG by blocking LD-induced SHP-1 activation potentiated PI3K-Akt signaling to drive Runx-mediated CD40 upregulation. Adoptive transfer experiments further showed that Runx1 and Runx3 play a pivotal role in eliciting antileishmanial immune response of SAG-treated DCs in vivo by promoting CD40-mediated type-1 T cell responses. Importantly, antimony-resistant LD suppressed SAG-induced CD40 upregulation on DCs by blocking the PI3K-Akt-Runx pathway through sustained SHP-1 activation. These findings unveil an immunoregulatory role for Runx proteins during LD infection.
Highlights
Dendritic cells (DCs) have emerged as key regulators of host immune response during visceral leishmaniasis (VL), a potentially fatal human disease caused by Leishmania donovani (LD)
bone marrow-derived DCs (BMDCs) infection with LDPm or LDAm resulted in a temporal reduction in LPS-stimulated CD40-expressing vector (CD40) expression, with maximum inhibition occurring at 24 h postinfection (Fig 1A and 1B, S1A and S1B Fig)
The LPS-stimulated CD40 expression was found to be lower on splenic DCs derived from LD-infected mice than those derived from uninfected mice (Fig 1C)
Summary
Dendritic cells (DCs) have emerged as key regulators of host immune response during visceral leishmaniasis (VL), a potentially fatal human disease caused by Leishmania donovani (LD). Besides functioning as initiators of Leishmania-specific T cell reactivity, DCs play a central role in the regulation of host-protective T helper cell type-1 (Th1) responses [1,2]. This regulatory potential of DCs is largely influenced by the level of CD40 expression on their surface [3]. DC-derived IL-12 skews differentiation of naïve CD4+ T cells to interferon gamma (IFNγ)-producing Th1 cells and thereby mounts protective immunity against LD infection [2,6] This scenario occurs only when CD40 is expressed at higher levels on DCs [7]. Identification of new transcriptional regulators for CD40 and deciphering their roles in LD-mediated regulation of CD40 expression in DCs may provide new insights into the immunoregulatory events involved in VL
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