Awasthi A, Riol-Blanco L, Jager A et al.Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 182:5904-5908

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2009; 182(10):5904-8. DOI: 10.4049/jimmunol.0900732
Source: PubMed


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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Available from: Caroline Pot, Jan 22, 2014
    • "We (Bettelli et al., 2006) and others (Mangan et al., 2006; Veldhoen et al., 2006) found that two cytokines, IL-6 and TGF-b1, can differentiate naive T cells into Th17 cells in vitro, although these cells are poor inducers of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for human multiple sclerosis. Exposure to the pro-inflammatory cytokine IL-23 can transform these cells into disease-inducing pathogenic Th17 cells (Awasthi et al., 2009; Cua et al., 2003; Jä ger et al., 2009; Langrish et al., 2005; McGeachy et al., 2007; McGeachy et al., 2009). Other cytokine combinations such as IL-1b+IL-6+IL-23 (Chung et al., 2009; Ghoreschi et al., 2010) or TGF-b3+IL-6+IL- 23 (Lee et al., 2012) can also induce Th17 cells that elicit EAE with severe tissue inflammation. "
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    ABSTRACT: Th17 cells play a critical role in host defense against extracellular pathogens and tissue homeostasis but can induce autoimmunity. The mechanisms implicated in balancing "pathogenic" and "non-pathogenic" Th17 cell states remain largely unknown. We used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells. Although CD5L does not affect Th17 differentiation, it is a functional switch that regulates the pathogenicity of Th17 cells. Loss of CD5L converts non-pathogenic Th17 cells into pathogenic cells that induce autoimmunity. CD5L mediates this effect by modulating the intracellular lipidome, altering fatty acid composition and restricting cholesterol biosynthesis and, thus, ligand availability for Rorγt, the master transcription factor of Th17 cells. Our study identifies CD5L as a critical regulator of the Th17 cell functional state and highlights the importance of lipid metabolism in balancing immune protection and disease induced by T cells.
    No preview · Article · Nov 2015 · Cell
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    • "The IL-23p19 or IL-23R knockout mice were resistant to EAE. IL-23R is also expressed in the central nervous system by infiltrated macrophages, and macrophages expressing IL-23R in response to IL-17, IL-22, and IL-23 release (Awasthi et al., 2009; Cua et al., 2003; McGeachy et al., 2009). Therapeutic treatment with Anti-IL-23p19 can reduced the IL-17 serum level as well as mRNA expression of IL-6, IL-17, TNF, IFN-c, and Interferon gamma-induced protein-10 (IP-10) in central nervous system. "
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    ABSTRACT: Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disease with unknown etiology and variable clinical evolution. Interleukin-23 (IL-23), a member of the IL-12 cytokine family is a heterodimeric cytokine composed of the IL-12p40 subunit, and with a novel p19 subunit, its ability to enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses. Objective: The objective of the project is to measure IL-23 level in plasma of multiple sclerosis (MS) patients in comparison with healthy control subjects. Methods: In a case-control study, plasma was collected from healthy subjects as control group (n = 40) and patients with relapsing remitting multiple sclerosis (RRMS) (n = 40). The plasma level of IL-23 was assessed by ELISA method. Statistical analysis was performed with SPSS (Ver. 16). Results: Plasma level of IL-23 in MS patients was significantly increased compared to control subjects (p Value < 0.001). Conclusions: Our findings revealed the increased IL-23 level in patients' group. In conclusion, the inhibition of IL-23 might be a novel and promising therapeutic strategy, especially in the therapy of autoimmune inflammatory diseases. IL-23 plays a pivotal role in development of MS and might be a specific marker and therapeutic target for MS.
    Full-text · Article · Aug 2014 · Immunological investigations
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    • "Among the CD4 T-cells, interleukin 17 (IL-17) producing T helper 17 (Th17) cell has a pivotal role in harmony with the natural and acquired immune responses to the extracellular bacteria and fungi[6] and also in the pathogenesis of several autoimmune and inflammatory disorders.[7] The retinoic acid receptor-related orphan receptor C2 (RORC2) transcription factor and IL-23R are expressed by the Th17 cells.[789] Development of Th17 cells and expression of their specific cytokines IL-17A and IL-17F are promoted by the RORC2.[10] "
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    ABSTRACT: Background: Common variable immunodeficiency (CVID) is characterized by a deficiency in the immune system with a heterogeneous collection of disorders resulting in antibody deficiency and recurrent infections. T helper 17 (Th17) cells promote B-cell survival and synergize with the B-cell activating factor to induce their differentiation into the plasma cells. A sub-population of innate lymphoid cells (ILCs) also produces interleukin 17 (IL-17). This study aimed to measure the Th17 specific genes and ILCs counts in the CVID patients in comparison with control subjects. Materials and Methods: Total messenger ribonucleic acid (mRNA) was extracted from the whole blood samples of 10 CVID patients and 10 healthy individuals. IL-17, retinoic acid receptor-related orphan receptor C2 (RORC2), IL-23R, and IL-9 gene expression were measured using the quantitative reverse transcriptase polymerase chain reaction. Count of lineage negative/CD127+/CD90+ ILCs in the blood samples was performed by the flow cytometry method. Results: The transcript levels of IL-17 and RORC2 in CVID patients was strongly lower than control subjects (P = 0.049 and P = 0.046, respectively), but slight reduction in the IL-23R expression (P = 0.252) have seen in the CVID patients. Accordingly, the number of ILCs decreased significantly (P = 0.04). Interestingly, IL-9 mRNA level was more significantly in the CVID patients (P = 0.001). Conclusions: The results presented in this study show that the Th17 cell specific genes expression (as the determiner Th17 cells) and ILCs (another lymphoid source of IL-17) are decreased in patients with CVID and this could be an explanation for the defect of their humoral immune response. In addition, elevation of the IL-9 gene expression may shed a new light into the way toward the understanding of the mechanism of autoimmunity in the CVID patients.
    Full-text · Article · Mar 2014 · Journal of research in medical sciences
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