The C5a/C5aR axes as novel regulators of natural killer (NK) cell functions

Toxoplasma gondii (T. gondii) is a protozoan parasite of global importance that infects rodents as part of its natural transmission cycle and induces disease in humans. Specifically, T. gondii is of medical importance in immunocompromised individuals, such as patients with AIDS. In otherwise healthy adults, this intracellular parasite is usually controlled by the immune system and remains in a dormant state in the brain by forming cysts. In mice the immune response against T. gondii is mainly induced through recognition of T. gondii-derived profilin by the Toll-like receptors (TLR) 11 and 12 expressed in splenic CD8α+ dendritic cells (DCs). So far, only a few studies have started to evaluate the contribution of C5aR1 and C5aR2 to the pathogenesis of T. gondii infection. We are investigating the crosstalk between these receptors for C5a and the induction of immune responses in NK cells using a mouse model of intraperitoneal T. gondii infection. Here, we work on an important not yet appreciated role of the C5a/C5aR axes for the early IFN-γ response and the control of T. gondii infection in the brain.

Uterine natural killer (uNK) cells are known to be important for placental angiogenesis and development during the first trimester of pregnancy. They are the main source for IFN-γ and angiogenic factors (VEGF, PLGF). Previous studies suggested a role for uNK cells in the pathogenesis of preeclampsia. We have recently shown that peripheral NK (pNK) cells express the complement receptor C5aR2, but not C5aR1 (Karsten et al. J. Immunol. 2017). While C5aR1 acts in a pro-inflammatory manner, the function of C5aR2 is still unclear. Recently, we have shown that the IFN-γ production by pNKs is highly dependent on the expression of C5aR2. In this project we are focusing on the regulatory role for the anaphylatoxin receptor C5aR2 in controlling the NK cell compartment in the uterus and subsequently its role in the outcome of pregnancy.

Figure 1: Organization of the normal pregnant (a-c) and the abortive (d-g) mouse uterus of BALB/c females mated by C57BL/6 males (early second half of pregnancy). Shown are a schematic summary and immunofluorescence stainings of the infiltrating leukocyte types and distribution patterns of vascular adhesion molecules in normal and abortive uteri. The invasive epithelial trophoblast (T), which intercalates itself in a complex fashion with other cell types, is marked with anti-mouse cytokeratin monoclonal antibodies (green). In normal pregnancies the maternal blood vessels of the vascular zone display P-selectin, MAdCAM-1 and VCAM-1 at this stage of gestation (a). These vessels contain, besides other leukocytes, significant numbers of granulocytes. The trophoblast does not express P-selectin (a, b). Within the trophoblast granulocytes are limited to maternal blood sinusoids of the outer trophoblast region (a, c). Uteri obtained from spontaneous abortions of BALB/c females mated by C57BL/6 males are characterized by a strong upregulation of P-selectin expression on maternal vascular zone vessels (d, bold red line) as well as on the fetal trophoblast mainly at sites of degeneration (d, red shading; e). Up-regulation of P-selectin is associated with a dramatic infiltration of activated Gr-1+ granulocytes (f). Activation of these cells is characterized by high expression of CD11b (g). (from Karsten et al. 2008)