Effects of Leishmania major clones showing different levels of virulence on infectivity, differentiation and maturation of human dendritic cells

Abstract

SummaryLeishmania parasites and dendritic cell interactions (DCs) play an essential role in initiating and directing T cell responses and influence disease evolution. These interactions may vary depending on Leishmania species and strains. To evaluate the correlation between Leishmania major (Lm) virulence and in-vitro human DC response, we compared the ability of high (HV) and low virulent (LV) Lm clones to invade, modulate cytokine production and interfere with differentiation of DCs. Clones derived from HV and LV (HVDlmpdi and LVDlmpdi), and deleted for the gene coding for a Lm protein disulphide isomerase (LmPDI), probably involved in parasite natural pathogenicity, were also used. Unlike LV, which fails to invade DCs in half the donors, HV promastigotes were associated with a significant increase of the infected cells percentage and parasite burden. A significant decrease of both parameters was observed in HVDlmpdi-infected DCs, compared to wild-type cells. Whatever Lm virulence, DC differentiation was accompanied by a significant decrease in CD1a expression. Lm clones decreased interleukin (IL)-12p70 production similarly during lipopolysaccharide (LPS)-induced maturation of DCs. LPS stimulation was associated with a weak increase in tumour necrosis factor (TNF)-a and IL-10 productions in HV-, HVDlmpdi-and LVDlmpdi-infected DCs. These results indicate that there is a significant variability in the capacity of Lm clones to infect human DCs which depends upon their virulence, probably involving LmPDI protein. However, independently of their virulence, Lm clones were able to down-regulate CD1a expression during DC differentiation and IL-12p70 production during DC maturation, which may favour their survival.

Immunomodulatory Effects of Four Leishmania infantum Potentially Excreted/Secreted Proteins on Human Dendritic Cells Differentiation and Maturation

“…major , L . donovani [ 46 – 48 ] and L . amazonensis [ 49 ] promastigotes were able to significantly downregulate CD1a expression on human DCs.…”

“…LipESP also induced significant levels of TNF-α and IL-10 in both cell populations with significantly higher cytokine-inducing capacities for LiP15 and LiAAA-ATPase. In vitro infection studies have mainly showed that in the absence of other stimuli, Leishmania parasites can trigger relatively weak or no cytokine production by DCs [ 21 , 48 , 52 – 54 ]. Similarly to our results, IL-12 production by infected DCs can be markedly enhanced by the addition of exogenous stimuli such as IFN-γ, IFN-γ/LPS, and CD40L [ 52 – 54 ].…”

The immune microenvironment in cutaneous leishmaniasis

“…The effect of Leishmania organisms on different inflammatory cells involves inhibition of dendritic cell maturation, differentiation and migration . In the presence of a high parasitic index, specifically, L. major causes further downregulation of CD1a with inhibition of Langerhans cell interleukin 12 production and resultant attenuation of the Th1 response. Due to the low interferon‐Υ, both CD80 and CD86 are downregulated on Langerhans cells causing minimal inhibition of the cytotoxic T‐lymphocyte antigen‐4 receptor on double‐negative T‐regulatory cells.…”

“…The effect of Leishmania organisms on different inflammatory cells involves inhibition of dendritic cell maturation, differentiation and migration. 33,51,52 In the presence of a high parasitic index, specifically, L. major causes further downregulation of CD1a with inhibition of Langerhans cell interleukin 12 production 40 (Fig. 6).…”

“…Initially, at a low parasitic index, Langerhans cells assume the role of antigen-presenting cells concomitantly secreting cytokines, such as interleukin 12, that result in activation of CD4 T cells and the Th1 response. 40 Activated CD4 T cells produce various lymphokines including interferon-c, interleukin 17 and interleukin 4. 41,42 Interferon-c induces expression of the costimulatory molecules CD86 and CD80 on Langerhans cells, resulting in inhibition of double-negative T-regulatory cells.…”