Runx proteins mediate protective immunity against Leishmania donovani infection by promoting CD40 expression on dendritic cells

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. Visceral leishmaniasis (VL), caused by Leishmania donovani, is the second most deadly parasitic disease in the world after malaria. The protective immunity against this disease largely depends on the level of CD40 (a cell surface protein) expression on a specialized group of immune cells called “dendritic cells” (DCs), which play a central role in initiating antileishmanial immune responses. Accordingly, to develop an improved immunological approach for the treatment/prevention of VL, it is important to understand the molecular events that favor the induction of CD40 expression on DCs. However, the molecular mechanisms controlling CD40 expression are not yet fully understood. Our work describes, for the first time, that the transcription factors Runx1 and Runx3 promote CD40 expression on DCs, which thereby potentiate the ability of DCs to induce antileishmanial immune responses in vivo. Our study thus provides new insights into the molecular mechanism required for an immune response to combat VL.