Silent infection of bone marrow-derived dendritic cells byLeishmania mexicana amastigotes

Abstract

Resolution of infection by Leishmania sp. is critically dependent on activation of CD4+ T helper cells. Naive CD4+ T helper cells are primed by dendritic cells which have responded to an activation signal in the periphery. However, the role of Leishmania‐infected dendritic cells in the activation of an anti‐Leishmania immune response has not been comprehensively addressed. Using the highly controlled model system of bone marrow‐derived dendritic cell infection by Leishmania mexicana cultured in vitro, we show that uptake of L. mexicana parasites does not result in activation of immature dendritic cells or secretion of IL‐12. Incubation with L. mexicana promastigotes results in the activation of a small percentage of dendritic cells which do not appear to contain whole parasites. Activation of dendritic cells is not suppressed by infection, since infected cells can be fully activated on addition of activating stimuli. Therefore, uptake of intact Leishmania mexicana parasites is not sufficient to activate dendritic cells in vitro. We propose that these data provide a basis for interpreting the interactions between dendritic cells and all Leishmania sp.

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

“…1). Similar results were previously reported in DCs infected with L. mexicana pro-and amastigotes (Bennett et al, 2001). A possible explanation for differential responses of DCs to these two stages of parasites forms is that lipophosphoglycan (LPG), the major surface molecules on promastigotes, can activate the TLR2-mediated signaling and, further, the near absence of LPG on amastigotes is responsible for the lack of DC activation (Beverley and Turco, 1998;de Veer et al, 2003).…”

“…Infection with L. major or L. donovani pro-or amastigotes, DCs can induce IL-12p40 production in vitro and in vivo (Bennett et al, 2001;Gorak et al, 1998;Konecny et al, 1999). However, we found that La promastigotes only weakly induced IL-12p40 production, whereas infection of amastigotes was devoid of this response (Fig.3B).…”

“…However, studies from our and other groups have revealed marked differences in DC responsiveness to Old World versus New World Leishmania parasites. For example, while appreciable levels of IL-12 are produced in murine DCs infected with L. major or L. donovani promastigotes (Gorak et al, 1998;von Stebut et al, 1998), C57BL/6 (B6) DCs infected with L. mexicana amastigotes show no sign of activation and no detectable levels of IL-12 and other proinflammatory cytokines (Bennett et al, 2001). Likewise, Leishnahia amazonensis (La) amastigotes failed to induce CD40-dependent IL-12 production from both BALB/c and C3H DCs (Qi et al, 2001).…”

A critical role for lipophosphoglycan in proinflammatory responses of dendritic cells to Leishmania mexicana

“…BMDC exposed to lpg1 -/-promastigotes up-regulated surface CD86 and MHC class II expression slightly but not statistically significantly. This was therefore reminiscent of the response of BMDC exposed to L. mexicana amastigotes [18].…”

“…We previously noted that exposure to L. mexicana promastigotes stimulates maturation of a fraction of bone marrow-derived DC (BMDC), whereas L. mexicana amastigotes do not induce DC activation, as indicated by MHC class II, CD86 and CD54 expression and IL-12p40 synthesis [18]. The nature of the L. mexicana promastigote-derived DC activating signal -a potential PAMPwas investigated here via a "candidate molecule" approach focusing on LPG.…”