Abstract
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.
Highlights
The development and function of immune lineages are regulated by cell-extrinsic cues provided by contact with other cells and microbes, the extracellular matrix, and soluble factors
We observed limited roles in steady-state lymphopoeisis and in antibody responses to virus infections, we found that GPR18 is required for the restoration of small intestine unconventional intraepithelial lymphocytes (IELs) following bone marrow transplantation
These analyses revealed that TCRγδ+ intestinal IELs, but not splenic TCRγδ+ cells, express high levels of Gpr18 (Fig 1A)
Summary
The development and function of immune lineages are regulated by cell-extrinsic cues provided by contact with other cells and microbes, the extracellular matrix, and soluble factors. Intestinal IELs contain several T cell subsets, including conventional CD4+ and CD8αβ+ TCRαβ+ cells and unconventional lymphocytes expressing CD8αα+ homodimers [2]. These CD8αα+ cells can be further segregated into TCRαβ+ and TCRγδ+ subsets [2,3,4]. Each of these subsets likely plays unique functional roles. TCRγδ+ IELs limit Salmonella typhimurium dissemination following infection and produce keratinocyte growth factor to mediate epithelial regeneration after injury [5,6,7,8,9,10]. The functional importance of IELs is increasingly becoming clear, the guidance cues which direct these specialized T cells to colonize the intestinal epithelium are not fully understood
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