Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor

Abstract

Visceral leishmaniasis (VL), a poverty-related disease caused by Leishmania donovani , is ranked by the World Health Organization as the second largest killer parasitic disease in the world. The protective immune response against VL is primarily regulated by dendritic cells (DCs), which upon activation/maturation initiate an antileishmanial immune response.

Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β

“…2E ). In addition, we have recently demonstrated an increased IL-10 production by BMDCs following LDAm infection ( 20 ). Accordingly, we verified whether IL-10 also plays a role in L. donovani -mediated suppression of CLEC-2 expression on DCs.…”

“…Finally, we determined whether CLEC-2 downregulation was responsible for impaired DC migration to lymph nodes in L. donovani -infected mice. In this regard, it is noteworthy that mice infected with L. donovani via the standard intravenous route ( 20 , 22 – 24 ) were not suitable for testing this hypothesis. This is because we studied DC trafficking from peripheral tissues to draining lymph nodes by injecting eFluor 670-labeled DCs into the hind footpads of syngeneic mice and analyzing the frequency of migrated DCs (eFluor 670 + DCs) in popliteal lymph nodes after 48 h. Unfortunately, we could not detect any parasite in the footpads of intravenously infected mice, although these parasites were readily detected in the spleen after 60 days of L. donovani infection (Fig.…”

“…Thus, TGF-β mediates the suppressive effect of L. donovani on CLEC-2 expression by DCs. Importantly, NF-κB activation in DCs is also inhibited by IL-10 produced during L. donovani infection ( 20 ). Based on this report from our group, one might question why L. donovani -induced IL-10 production failed to suppress CLEC-2 expression on DCs.…”

Malaria and leishmaniasis: Updates on co-infection

“…In this regard, several studies have shown that exposure to Plasmodium-infected erythrocytes or hemozoin, a product of hemoglobin metabolism, negatively interferes with the antigenpresenting function of dendritic cells (DCs) (78)(79)(80)(81)(82)(83)(84). This negative impact on DC activation and maturation is also described in studies evaluating the interaction of the promastigote form of Leishmania with DCs (85)(86)(87)(88)(89)(90)(91)(92). On the other hand, uptake of amastigote forms of Leishmania by DC induces its maturation and activation of T cells to a Th1 profile (92,93).…”