Cutting Edge: IL-23 Receptor GFP Reporter Mice Reveal Distinct Populations of IL-17-Producing Cells

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
The Journal of Immunology (Impact Factor: 5.36). 06/2009; 182(10):5904-8. DOI: 10.4049/jimmunol.0900732
Source: PubMed

ABSTRACT IL-23, an IL-12 family member, has been implicated in the development of Th17 cells and the progression of autoimmune diseases. However, due to the lack of availability of sensitive Ab reagents specific for the IL-23 receptor (IL-23R), it has been difficult to characterize the cell types that express the IL-23R and are responsive to IL-23 in vivo. To address the role of IL-23 in vivo, we have generated a novel "knock-in" mouse in which we have replaced the intracellular domain of the IL-23R with the GFP. We show that in addition to Th17 cells, a subset of myeloid cells express IL-23R and respond to IL-23 by producing IL-17 and IL-22. Our studies further demonstrate that IL-23R expression is crucial for generation of encephalitogenic Th17 cells, but its expression on the innate immune system is dispensible in the development of experimental autoimmune encephalomyelitis.

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    ABSTRACT: Interleukin (IL)-17 plays a key role in immunity. In acute infections, a rapid IL-17 response must be induced without prior antigen exposure, and γδ T cells are the major initial IL-17 producers. In fact, some γδ T cells make IL-17 within hours after an immune challenge. These cells appear to acquire the ability to respond to IL-1 and IL-23 and to make IL-17 naturally in naïve animals. They are known as the natural Tγδ17 (nTγδ17) cells. The rapidity of the nTγδ17 response, and the apparent lack of explicit T cell receptor (TCR) engagement for its induction have led to the view that this is a cytokine (IL-1, IL-23)-mediated response. However, pharmacological inhibition or genetic defects in TCR signaling drastically reduce the nTγδ17 response and/or their presence. To better understand antigen recognition in this rapid IL-17 response, we analyzed the antigen receptor repertoire of IL-1R(+)/IL-23R(+) γδ T cells, a proxy for nTγδ17 cells in naïve animals directly ex vivo, using a barcode-enabled high throughput single-cell TCR sequence analysis. We found that regardless of their anatomical origin, these cells have a highly focused TCR repertoire. In particular, the TCR sequences have limited V gene combinations, little or no junctional diversity and much reduced or no N region diversity. In contrast, IL-23R(-) cells at mucosal sites similar to most of the splenic γδ T cells and small intestine epithelial γδ lymphocytes expressed diverse TCRs. This remarkable commonality and restricted repertoire of IL-1R(+)/IL-23R(+) γδ T cells underscores the importance of antigen recognition in their establishment/function.
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    ABSTRACT: γδ T cells represent a small population of overall T lymphocytes (0.5-5%) and have variable tissue distribution in the body. γδ T cells can perform complex functions, such as immune surveillance, immunoregulation, and effector function, without undergoing clonal expansion. Heterogeneous distribution and anatomic localization of γδ T cells in the normal and inflamed tissues play an important role in alloimmunity, autoimmunity, or immunity. The cross-talk between γδ T cells and other immune cells and phenotypic and functional plasticity of γδ T cells have been given recent attention in the field of immunology. In this review, we discussed the cellular and molecular interaction of γδ T cells with other immune cells and its mechanism in the pathogenesis of various autoimmune diseases. © Society for Leukocyte Biology.

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