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
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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.
    Immunological investigations 08/2014; 44(1):1-9. DOI:10.3109/08820139.2014.930477 · 1.99 Impact Factor
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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.
    Journal of research in medical sciences 03/2014; 19(Suppl 1). · 0.65 Impact Factor
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    • "C57BL/6J mice (#664), IL-12Rβ2−/− (#3248), RORγt−/− (#7572) and Rag1−/− (#2216) on C57BL/6 background were purchased from the Jackson Laboratory. IL-12Rβ2−/−, IL-23R-eGFP+/− and IL-23R-eGFP homozygous mice [16] (referred to in the text as IL-23R−/−) were maintained on a C57BL/6 background. IL-23R−/− and IL-12Rβ2−/− were bred to Rag1−/− to respectively generate IL-23R−/−.Rag1−/− and IL-12Rβ2−/−.Rag1−/− mice. "
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    ABSTRACT: IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans.
    PLoS ONE 02/2014; 9(2):e89092. DOI:10.1371/journal.pone.0089092 · 3.23 Impact Factor
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