title: Mutated major histocompatibility complex class II transactivator up-regulates interleukin-33-dependent differentiation of Th2 subset through Nod2 binding for NLR (NOD-like receptor) signaling initiation.
abstract: Dominant-negative mutants of class II transactivator (mCIITAs) with N-terminal depletion have been used to repress the transcription of class II genes in xenotransplantation. Here, we report that mCIITA overexpressing myeloid cell line Ana-1 (Ana-1-mCIITA) derived from a C57BL/6 mouse was able to down-regulate the MHC class II expression and reverse immune responses from Th1 (IL-2(+)IFN-γ(+)STAT4(+)) to Th2 (IL-4(+)IL-5(+)IL-10(+)IL-13(+)STAT6(+)) when cocultured with T cells. Mechanism analysis indicated that the mCIITA protein is able to initiate a NOD-like receptor-related signaling pathway via binding of the cytoplasmic Nod2 protein, which was followed by activating RIP2, caspase 1, and IKK-α/β. This ensures the expression of the genes encoding the cytokines IL-33, IL-1β, and TNF-α; however, only the highly expressed IL-33 is responsible for inducing the type 2 response, with a skewed Th2 cytokine secretion (IL-4(+)IL-5(+)IL-10(+)IL-13(+)IL-2(-)IFN-γ(-)), which was completely prevented by the deactivation of the Nod2 gene with siRNA or by the blockage of the IL-33-related signaling using the mAb ST2L against the IL-33 receptor. mCIITA-mediated Th2 conversion was also successfully induced in vivo in a mCIITA-transgenic C57BL/6 mouse model. These results indicate that the Th1/Th2 balance could be regulated by an N terminus-depleted CIITA molecule via NOD-like receptor-related signaling, a property valuable for disease control, especially for inducing transplantation tolerance via the repression of class II expression and the attenuation of a Th1-dominant response.
authors.affiliation: Department of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gu
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Shao
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Zuoqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Electronic address: lulunew2003@163.com.
authors.forename: Liming
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Electronic address: kychouimm@sjtu.edu.cn.
authors.forename: Kuang-Yen
authors.initials: KY
authors.lastname: Chou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D023001:Transplantation Tolerance / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; C083728:MHC class II transactivator protein; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D020170:Caspase 1