The Ly49E Receptor Inhibits the Immune Control of Acute Trypanosoma cruzi Infection

Abstract

The protozoan parasite Trypanosoma cruzi circulates in the blood upon infection and invades various cells. Parasites intensively multiply during the acute phase of infection and persist lifelong at low levels in tissues and blood during the chronic phase. Natural killer (NK) and NKT cells play an important role in the immune control of T. cruzi infection, mainly by releasing the cytokine IFN-γ that activates the microbicidal action of macrophages and other cells and shapes a protective type 1 immune response. The mechanisms by which immune cells are regulated to produce IFN-γ during T. cruzi infection are still incompletely understood. Here, we show that urokinase plasminogen activator (uPA) is induced early upon T. cruzi infection and remains elevated until day 20 post-infection. We previously demonstrated that the inhibitory receptor Ly49E, which is expressed, among others, on NK and NKT cells, is triggered by uPA. Therefore, we compared wild type (WT) to Ly49E knockout (KO) mice for their control of experimental T. cruzi infection. Our results show that young, i.e., 4- and 6-week-old, Ly49E KO mice control the infection better than WT mice, indicated by a lower parasite load and less cachexia. The beneficial effect of Ly49E depletion is more obvious in 4-week-old male than in female mice and weakens in 8-week-old mice. In young mice, the lower T. cruzi parasitemia in Ly49E KO mice is paralleled by higher IFN-γ production compared to their WT controls. Our data indicate that Ly49E receptor expression inhibits the immune control of T. cruzi infection. This is the first demonstration that the inhibitory Ly49E receptor can interfere with the immune response to a pathogen in vivo.

Ly49E separates liver ILC1s into embryo-derived and postnatal subsets with different functions

“…Studies have shown that Ly49E is not involved in several pathophysiological situations, including malaria infection ( Filtjens et al, 2014 ), chemically induced colitis ( Van Acker et al, 2016 ), and different tumors ( Filtjens et al, 2016b ). However, young Ly49E-KO mice could control the parasite infection better ( Filtjens et al, 2016a ). Although Ly49E activation by uPA, a non-MHC class I ligand ( Van Den Broeck et al, 2008 ), could inhibit the effector functions of NK cell lines or fetal thymic NK cells, freshly isolated liver group 1 ILCs from Ly49E-deficient and WT mice did not differ in cytotoxic capacity in the presence of uPA ( Filtjens et al, 2013 ).…”

Natural Killer Cell Integrins and Their Functions in Tissue Residency

“…Liver trNK cells in mice are also functionally unique as they exhibit a higher level of baseline activation relative to splenic or liver cNK cells ( 56 ). They are larger and more granular, and express Ly49E, which mediates responses to liver-specific infections such as T. cruzi ( 173 ). Cytokine release is more efficient from these cells, TNFα, GM-CSF and IL-2 are all increased, and their high expression of TRAIL and FasL makes them better at inducing target cell apoptosis by alternative killing.…”

The transcription factor RUNX2 drives the generation of human NK cells and promotes tissue residency

“…At 6–7 weeks post-injection, the mice were sacrificed by cervical dislocation and perfused with PBS. Single-cell suspensions of liver, spleen, bone marrow, and intestinal LPL were generated as previously described ( Van Acker et al, 2017 ; Filtjens et al, 2016 ; Filtjens et al, 2013 ). Lungs were cut in pieces and digested in RPMI1640 (Life Technologies) supplemented with 2% FCS, collagenase D (2 mg/mL, Roche), and Dnase I (0.2 mg/mL, Roche).…”