Vai trò quan trọng của protein gắn methyl-CpG Mbd2 trong việc kiểm soát sự kích hoạt Th2 bởi các tế bào dendritic
Tóm tắt
Các tế bào dendritic (DCs) điều hướng sự phân biệt của tế bào T CD4+ thành các nhóm tế bào trợ giúp (Th) khác nhau, cần thiết cho việc bảo vệ chống lại các bệnh nhiễm trùng đa dạng. Tuy nhiên, các cơ chế mà DCs sử dụng để thúc đẩy phản ứng Th2, điều quan trọng cả cho miễn dịch đối với nhiễm giun và trong các bệnh dị ứng, hiện vẫn chưa được hiểu rõ. Chúng tôi chứng minh vai trò quan trọng của protein miền gắn methyl-CpG-2 (Mbd2), liên kết giữa methyl hóa DNA với cấu trúc nhiễm sắc thể ức chế, trong việc điều chỉnh biểu hiện của một loạt các gen liên quan đến kích hoạt và chức năng tối ưu của DC. Trong trường hợp thiếu Mbd2, DCs thể hiện sự kích hoạt kiểu hình giảm và có khả năng đáng kể để khởi động miễn dịch Th2 chống lại giun hoặc dị nguyên bị suy giảm. Dữ liệu này xác định một cơ chế di truyền học trung tâm đối với sự kích hoạt phản ứng tế bào T CD4+ bởi DCs, đặc biệt trong bối cảnh Th2, và tiết lộ các protein gắn methyl-CpG cùng với các gen dưới sự kiểm soát của chúng như là những mục tiêu điều trị tiềm năng cho viêm loại 2.
Từ khóa
#Dendritic cells #Th2 response #Mbd2 #immune activation #epigenetic mechanismsTài liệu tham khảo
Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).
Kapsenberg, M. L. Dendritic-cell control of pathogen-driven T-cell polarization. Nat. Rev. Immunol. 3, 984–993 (2003).
Kool, M., Hammad, H. & Lambrecht, B. N. Cellular networks controlling Th2 polarization in allergy and immunity. F1000 Biol. Rep. 4, 6 (2012).
Gause, W. C., Wynn, T. A. & Allen, J. E. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat. Rev. Immunol. 13, 607–614 (2013).
Hammad, H. et al. Inflammatory dendritic cells--not basophils--are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J. Exp. Med. 207, 2097–2111 (2010).
Ohnmacht, C. et al. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 33, 364–374 (2010).
Phythian-Adams, A. T. et al. CD11c depletion severely disrupts Th2 induction and development in vivo. J. Exp. Med. 207, 2089–2096 (2010).
MacDonald, A. S. & Maizels, R. M. Alarming dendritic cells for Th2 induction. J. Exp. Med. 205, 13–17 (2008).
Pulendran, B., Tang, H. & Manicassamy, S. Programming dendritic cells to induce T(H)2 and tolerogenic responses. Nat. Immunol. 11, 647–655 (2010).
MacDonald, A. S., Straw, A. D., Dalton, N. M. & Pearce, E. J. Cutting edge: Th2 response induction by dendritic cells: a role for CD40. J. Immunol. 168, 537–540 (2002).
Whelan, M. et al. A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J. Immunol. 164, 6453–6460 (2000).
Jember, A. G., Zuberi, R., Liu, F. T. & Croft, M. Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40. J. Exp. Med. 193, 387–392 (2001).
Jenkins, S. J., Perona-Wright, G., Worsley, A. G., Ishii, N. & MacDonald, A. S. Dendritic cell expression of OX40 ligand acts as a costimulatory, not polarizing, signal for optimal Th2 priming and memory induction in vivo. J. Immunol. 179, 3515–3523 (2007).
Medoff, B. D. et al. CD11b+ myeloid cells are the key mediators of Th2 cell homing into the airway in allergic inflammation. J. Immunol. 182, 623–635 (2009).
Cook, P. C. et al. Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo. Proc. Natl Acad. Sci. USA 109, 9977–9982 (2012).
Agrawal, S. et al. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol. 171, 4984–4989 (2003).
Artis, D. et al. Dendritic cell-intrinsic expression of NF-kappa B1 is required to promote optimal Th2 cell differentiation. J. Immunol. 174, 7154–7159 (2005).
Gao, Y. et al. Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39, 722–732 (2013).
Williams, J. W. et al. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat. Commun. 4, 2990 (2013).
Bell, B. D. et al. The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat. Immunol. 14, 364–371 (2013).
Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91–105 (2009).
Kanno, Y., Vahedi, G., Hirahara, K., Singleton, K. & O’Shea, J. J. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu. Rev. Immunol. 30, 707–731 (2012).
Fang, T. C. et al. Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J. Exp. Med. 209, 661–669 (2012).
Alvarez-Errico, D., Vento-Tormo, R., Sieweke, M. & Ballestar, E. Epigenetic control of myeloid cell differentiation, identity and function. Nat. Rev. Immunol. 15, 7–17 (2014).
Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31, 89–97 (2006).
Menafra, R. & Stunnenberg, H. G. MBD2 and MBD3: elusive functions and mechanisms. Front. Genet. 5, 428 (2014).
Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).
Berger, J. & Bird, A. Role of MBD2 in gene regulation and tumorigenesis. Biochem. Soc. Trans. 33, 1537–1540 (2005).
Hutchins, A. S. et al. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol. Cell. 10, 81–91 (2002).
Hutchins, A. S. et al. Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity. J. Immunol. 175, 5606–5610 (2005).
Kersh, E. N. Impaired memory CD8 T cell development in the absence of methyl-CpG-binding domain protein 2. J. Immunol. 177, 3821–3826 (2006).
Wang, L. et al. Mbd2 promotes foxp3 demethylation and T-regulatory-cell function. Mol. Cell. Biol. 33, 4106–4115 (2013).
Kzhyshkowska, J. et al. Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J. Immunol. 176, 5825–5832 (2006).
Stober, C. B., Brode, S., White, J. K., Popoff, J. F. & Blackwell, J. M. Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function. Infect. Immun. 75, 5059–5067 (2007).
Song, L., Lee, C. & Schindler, C. Deletion of the murine scavenger receptor CD68. J. Lipid Res. 52, 1542–1550 (2011).
Prabakaran, T. et al. Mannose 6-phosphate receptor and sortilin mediated endocytosis of alpha-galactosidase A in kidney endothelial cells. PLoS One 7, e39975 (2012).
Baubec, T., Ivanek, R., Lienert, F. & Schubeler, D. Methylation-dependent and -independent genomic targeting principles of the MBD protein family. Cell 153, 480–492 (2013).
Scholer, A., Hugues, S., Boissonnas, A., Fetler, L. & Amigorena, S. Intercellular adhesion molecule-1-dependent stable interactions between T cells and dendritic cells determine CD8+ T cell memory. Immunity 28, 258–270 (2008).
Nayak, J. V. et al. Phagocytosis induces lysosome remodeling and regulated presentation of particulate antigens by activated dendritic cells. J. Immunol. 177, 8493–8503 (2006).
Perona-Wright, G. et al. Concurrent bacterial stimulation alters the function of helminth-activated dendritic cells, resulting in IL-17 induction. J. Immunol. 188, 2350–2358 (2012).
Pearce, E. J. & MacDonald, A. S. The immunobiology of schistosomiasis. Nat. Rev. Immunol. 2, 499–511 (2002).
Larkin, B. M. et al. Induction and regulation of pathogenic Th17 cell responses in schistosomiasis. Semin. Immunopathol. 34, 873–888 (2012).
Caton, M. L., Smith-Raska, M. R. & Reizis, B. Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J. Exp. Med. 204, 1653–1664 (2007).
Mohrs, K., Wakil, A. E., Killeen, N., Locksley, R. M. & Mohrs, M. A two-step process for cytokine production revealed by IL-4 dual-reporter mice. Immunity 23, 419–429 (2005).
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Gregory, L. G. & Lloyd, C. M. Orchestrating house dust mite-associated allergy in the lung. Trends Immunol. 32, 402–411 (2011).
Barrett, N. A. et al. Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes. J. Exp. Med. 208, 593–604 (2011).
Lambrecht, B. N. & Hammad, H. Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu. Rev. Immunol. 30, 243–270 (2012).
Gunther, K. et al. Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. Nucleic Acids Res. 41, 3010–3021 (2013).
MacDonald, A. S., Straw, A. D., Bauman, B. & Pearce, E. J. CD8- dendritic cell activation status plays an integral role in influencing Th2 response development. J. Immunol. 167, 1982–1988 (2001).
Yoshizaki, A. et al. Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model. J. Immunol. 185, 2502–2515 (2010).
Polte, T., Jagemann, A., Foell, J., Mittler, R. S. & Hansen, G. CD137 ligand prevents the development of T-helper type 2 cell-mediated allergic asthma by interferon-gamma-producing CD8+ T cells. Clin. Exp. Allergy 37, 1374–1385 (2007).
Vander Lugt, B. et al. Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation. Nat. Immunol. 15, 161–167 (2014).
Posselt, G., Schwarz, H., Duschl, A. & Horejs-Hoeck, J. Suppressor of cytokine signaling 2 is a feedback inhibitor of TLR-induced activation in human monocyte-derived dendritic cells. J. Immunol. 187, 2875–2884 (2011).
Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V. A. & Bird, A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 15, 710–723 (2001).
Madan, R. et al. Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J. Immunol. 183, 2312–2320 (2009).
Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326 (2001).
Huber, W. et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat. Methods 12, 115–121 (2015).
Kauffmann, A. & Huber, W. Microarray data quality control improves the detection of differentially expressed genes. Genomics 95, 138–142 (2010).
Du, P., Kibbe, W. A. & Lin, S. M. lumi: a pipeline for processing Illumina microarray. Bioinformatics 24, 1547–1548 (2008).
Barrett, T. et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 41, D991–D995 (2013).
Schmiedeberg, L., Skene, P., Deaton, A. & Bird, A. A temporal threshold for formaldehyde crosslinking and fixation. PLoS One 4, e4636 (2009).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
Deaton, A. M. et al. Cell type-specific DNA methylation at intragenic CpG islands in the immune system. Genome Res. 21, 1074–1086 (2011).
Matthews, S. A. et al. Protein kinase D isoforms are dispensable for integrin-mediated lymphocyte adhesion and homing to lymphoid tissues. Eur. J. Immunol. 42, 1316–1326 (2012).