title: NK-, NKT- and CD8-Derived IFNγ Drives Myeloid Cell Activation and Erythrophagocytosis, Resulting in Trypanosomosis-Associated Acute Anemia.
abstract: African trypanosomes are the causative agents of Human African Trypanosomosis (HAT/Sleeping Sickness) and Animal African Trypanosomosis (AAT/Nagana). A common hallmark of African trypanosome infections is inflammation. In murine trypanosomosis, the onset of inflammation occurs rapidly after infection and is manifested by an influx of myeloid cells in both liver and spleen, accompanied by a burst of serum pro-inflammatory cytokines. Within 48 hours after reaching peak parasitemia, acute anemia develops and the percentage of red blood cells drops by 50%. Using a newly developed in vivo erythrophagocytosis assay, we recently demonstrated that activated cells of the myeloid phagocytic system display enhanced erythrophagocytosis causing acute anemia. Here, we aimed to elucidate the mechanism and immune pathway behind this phenomenon in a murine model for trypanosomosis. Results indicate that IFNγ plays a crucial role in the recruitment and activation of erythrophagocytic myeloid cells, as mice lacking the IFNγ receptor were partially protected against trypanosomosis-associated inflammation and acute anemia. NK and NKT cells were the earliest source of IFNγ during T. b. brucei infection. Later in infection, CD8+ and to a lesser extent CD4+ T cells become the main IFNγ producers. Cell depletion and transfer experiments indicated that during infection the absence of NK, NKT and CD8+ T cells, but not CD4+ T cells, resulted in a reduced anemic phenotype similar to trypanosome infected IFNγR-/- mice. Collectively, this study shows that NK, NKT and CD8+ T cell-derived IFNγ is a critical mediator in trypanosomosis-associated pathology, driving enhanced erythrophagocytosis by myeloid phagocytic cells and the induction of acute inflammation-associated anemia.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Department of Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cnops
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Department of Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium.
authors.forename: Carl
authors.initials: C
authors.lastname: De Trez
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Department of Myeloid Cell Immunology, VIB, Brussels, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Stijlemans
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Department of Myeloid Cell Immunology, VIB, Brussels, Belgium.
authors.forename: Jiri
authors.initials: J
authors.lastname: Keirsse
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Department of Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium.
authors.forename: Florence
authors.initials: F
authors.lastname: Kauffmann
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa; Faculty of Health Sciences (IDM, Division Immunology), University of Cape Town, Cape Town, South Africa.
authors.forename: Mark
authors.initials: M
authors.lastname: Barkhuizen
authors.affiliation: Faculty of Health Sciences (IDM, Division Immunology), University of Cape Town, Cape Town, South Africa.
authors.forename: Roanne
authors.initials: R
authors.lastname: Keeton
authors.affiliation: Bioceros, Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa; Faculty of Health Sciences (IDM, Division Immunology), University of Cape Town, Cape Town, South Africa.
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Department of Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium; Faculty of Health Sciences (IDM, Division Immunology), University of Cape Town, Cape Town, South Africa.
authors.forename: Stefan
authors.initials: S
authors.lastname: Magez
mesh_terms: D019264:Adoptive Transfer; D000740:Anemia / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000150:complications / Q000276:immunology*
chemical_list: D007371:Interferon-gamma