SHP-1 contributes to the CD40 signaling reciprocity and controls Leishmania major infection

Abstract

Event Abstract Back to Event SHP-1 contributes to the CD40 signaling reciprocity and controls Leishmania major infection TABISH H. KHAN1* 1 National Centre for Cell Science, India CD40, a costimulatory molecule expressed on macrophages can induce counteractive immune responses depending on the intensity of CD40 crosslinking. A strong CD40 stimulation induces preferential phosphorylation of p38MAPK and pro-inflammatory cytokine IL-12 production whereas a weaker CD40 stimulation induces preferential phosphorylation of ERK-1/2 and anti-inflammatory cytokine IL-10 production. In the experimental infection with Leishmania major, CD40-induced p38MAPK activation and IL-12 expression are suppressed whereas ERK-1/2 activation and IL-10 expression are enhanced. We concluded that the observed reciprocity was due to differential phosphorylation of these two MAPKs and we propose that this observed reciprocity can be function of a phosphatase that dephosphorylates these MAPKs differentially. Leishmania infection activates a phosphotyrosine phosphatase SHP-1, which we propose to possibly play a role in MAPK dephosphorylation and thereby influences the reciprocity in CD40 signaling. Although CD40 plays important roles in L. major infection, whether SHP-1 influences CD40 signaling and affects L. major infection or vice versa have never been examined. In this report, we show that SHP-1 does contribute to the CD40 signaling reciprocity by differential p38MAPK and ERK-1/2 dephosphorylation. In L. major infection, SHP-1 phosphorylation and activity are increased causing reciprocal down-regulation of CD40-induced p38MAPK phosphorylation. SHP-1 overexpression renders the resistant C57BL/6 mice susceptible whereas its inhibition protects susceptible BALB/c mice to L. major infection. Thus, we demonstrate for the first time that SHP-1 contributes to the CD40 signaling reciprocity. These properties are exploited by the parasite to design the SHP-1-targeted immune evasion strategy ensuring their survival in a mammalian host.