Early Cellular Pathways of Mouse Natural Killer Cell Development.

Natural killer (NK) cells are large granular lymphocytes that are components of the innate immune system. These cells are key players in the defense against viral and other microbial infections and cancer and have an important function during pregnancy, autoimmunity and allergy. Furthermore, NK cells play important roles in hematopoietic stem cell (HSC) transplantation by providing the graft versus leukemia effect and preventing the development of graft versus host disease. Thus, understanding the developmental pathway(s) from multipotent HSCs to the NK cell lineage-restricted progenitors is of significant clinical value. However, despite extensive progress in the delineation of mature blood cell development, including the B- and T-cell lineages, the early stages of NK cell lineage commitment and development have been less well established and characterized. Here, I review the progress made thus far in dissecting the developmental stages, from HSCs in the bone marrow to the lineage-committed NK cells in mouse

GPR18 Controls Reconstitution of Mouse Small Intestine Intraepithelial Lymphocytes following Bone Marrow Transplantation.

Specific G protein coupled receptors (GPRs) regulate the proper positioning, function, and development of immune lineage subsets. Here, we demonstrate that GPR18 regulates the reconstitution of intraepithelial lymphocytes (IELs) of the small intestine following bone marrow transplantation. Through analysis of transcriptional microarray data, we find that GPR18 is highly expressed in IELs, lymphoid progenitors, and mature follicular B cells. To establish the physiological role of this largely uncharacterized GPR, we generated Gpr18-/- mice. Despite high levels of GPR18 expression in specific hematopoietic progenitors, Gpr18-/- mice have no defects in lymphopoiesis or myelopoiesis. Moreover, antibody responses following immunization with hapten-protein conjugates or infection with West Nile virus are normal in Gpr18-/- mice. Steady-state numbers of IELs are also normal in Gpr18-/- mice. However, competitive bone marrow reconstitution experiments demonstrate that GPR18 is cell-intrinsically required for the optimal restoration of small intestine TCRγδ+ and TCRαβ+ CD8αα+ IELs. In contrast, GPR18 is dispensable for the reconstitution of large intestine IELs. Moreover, Gpr18-/- bone marrow reconstitutes small intestine IELs similarly to controls in athymic recipients. Gpr18-/- chimeras show no changes in susceptibility to intestinal insults such as Citrobacter rodentium infections or graft versus host disease. These data reveal highly specific requirements for GPR18 in the development and reconstitution of thymus-derived intestinal IEL subsets in the steady-state and after bone marrow transplantation