成人T细胞白血病的表型研究进展
中国药科大学, 多靶标天然药物全国重点实验室, 江苏南京 211198
| 摘 要： | 人类T细胞白血病病毒1型（human T cell leukemia virus type 1, HTLV-1）是第一个被报道的人类逆转录病毒，绝大多数感染者终身无症状，但有少数会发展为成人T细胞白血病（adult T cell leukemia, ATL）。T细胞的生物标志物区分了不同的T细胞亚群，同时也反映了相应亚群不同的功能和分化途径。由于ATL细胞普遍表达调节T细胞（regulatory T cell, Treg）和辅助T细胞2型（type 2 T helper cell, Th2）分化和功能相关的生物标志物，因此一般认为ATL细胞具有Treg和Th2表型。但近年来研究发现ATL细胞表达更多不同T细胞分化相关基因，并且HTLV-1的癌基因对上述基因有着不同的调控，说明ATL的表型有待进一步研究探讨。ATL具有异质性，详细区分ATL的表型对研究疾病发展极为重要。本文介绍了四种常见CD4+ T细胞亚型的生物标志物，总结了HTLV-1的癌基因对它们的调控及其在ATL中的表达和功能，并探讨了ATL具有高异质性的可能机制。 |
| 关 键 词： | 成人T细胞白血病; T细胞表型; T细胞分化; HBZ; Tax |
| DOI： | 10.57237/j.mrf.2024.02.001 |
View:
Downloads:
收稿日期: 2024-04-03
接受日期: 2024-04-18
在线出版日期: 2024-04-24
Progress in the Phenotypic Study of Adult T-cell Leukemia
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| Abstract: | Human T-cell Leukemia Virus Type 1 (HTLV-1) is the first reported human retrovirus. While most of the HTLV-1 infected individuals remain lifelong asymptomatic, a small number of those will develop a malignancy named adult T-cell leukemia (ATL). T-cell biomarkers define distinct T-cell subsets and also reflect their functions and differentiation. Because ATL cells express Treg and Th2 associated biomarkers, they are considered to have a Treg/Th1 phenotype. However, recently it has been discovered that ATL cells express a broad array of genes related to T cell phenotype differentiation, and HTLV-1 oncogenes are deeply implicated in the regulation of ATL phenotype. ATL exhibits significant heterogeneity, and a detailed distinction of ATL phenotypes is extremely important for studying this malignancy. This review introduces the biomarkers of four common CD4+ T cell subtypes, summarizes the regulation of these biomarkers by HTLV-1 viral proteins, and their expression and function in ATL, and discusses the possible reasons for the high heterogeneity observed in ATL. |
| Keywords: | Adult T-cell Leukemia; T cell Phenotype; T Cell Differentiation; HBZ; Tax |
参考文献
| [1] | POIESZ B J, RUSCETTI F W, GAZDAR A F, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma [J]. Proceedings of the National Academy of Sciences, 1980, 77(12): 7415-9. |
| [2] | ZUO X, ZHOU R, YANG S, et al. HTLV-1 persistent infection and ATLL oncogenesis [J]. Journal of Medical Virology, 2023, 95(1): e28424. |
| [3] | FURUTA R, YASUNAGA J-I, MIURA M, et al. Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo [J]. PLoS Pathog, 2017, 13(11): e1006722. |
| [4] | SHIMOYAMA M, GROUP M O T L S. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma [J]. British Journal of Haematology, 1991, 79(3): 428-37. |
| [5] | TSUKASAKI K, TOBINAI K. Human T-cell lymphotropic virus type I-associated adult T-cell leukemi a-lymphoma: new directions in clinical research [J]. Clin Cancer Res, 20(20): 5217-25. |
| [6] | KARUBE K, OHSHIMA K, TSUCHIYA T, et al. Expression of FoxP3, a key molecule in CD4+CD25+ regulatory T cells, in adult T-cell leukaemia/lymphoma cells [J]. British Journal of Haematology, 2004, 126(1): 81-4. |
| [7] | SUGATA K, YASUNAGA J-I, KINOSADA H, et al. HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation [J]. Cancer Research, 2016, 76(17): 5068-79. |
| [8] | ZHAO T, SATOU Y, SUGATA K, et al. HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator [J]. Blood, 2011, 118(7): 1865-76. |
| [9] | TAMAKI T, KARUBE K, SAKIHAMA S, et al. A Comprehensive Study of the Immunophenotype and its Clinicopathologic Significance in Adult T-Cell Leukemia/Lymphoma [J]. Modern Pathology, 2023, 36(8). |
| [10] | SHIMAUCHI T, IMAI S, HINO R, et al. Production of thymus and activation-regulated chemokine and macrophage-derived chemokine by CCR4+ adult T-cell leukemia cells [J]. Clin Cancer Res, 2005, 11(6): 2427-35. |
| [11] | SARAVIA J, CHAPMAN N M, CHI H. Helper T cell differentiation [J]. Cellular & Molecular Immunology, 2019, 16(7): 634-43. |
| [12] | ZHU J. T Helper Cell Differentiation, Heterogeneity, and Plasticity [J]. Cold Spring Harb Perspect Biol, 2018, 10(10). |
| [13] | MOSMANN T R, COFFMAN R L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties [J]. Annu Rev Immunol, 1989, 7: 145-73. |
| [14] | MOSMANN T R, CHERWINSKI H, BOND M W, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins [J]. J Immunol, 1986, 136(7): 2348-57. |
| [15] | SZABO S J, SULLIVAN B M, PENG S L, et al. Molecular mechanisms regulating Th1 immune responses [J]. Annu Rev Immunol, 2003, 21: 713-58. |
| [16] | HSIEH C S, MACATONIA S E, TRIPP C S, et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages [J]. Science, 1993, 260(5107): 547-9. |
| [17] | THIERFELDER W E, VAN DEURSEN J M, YAMAMOTO K, et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells [J]. Nature, 1996, 382(6587): 171-4. |
| [18] | SZABO S J, KIM S T, COSTA G L, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment [J]. Cell, 2000, 100(6): 655-69. |
| [19] | LI Z, ZHANG Y, SUN B. Current understanding of Th2 cell differentiation and function [J]. Protein Cell, 2011, 2(8): 604-11. |
| [20] | GORDON S, MARTINEZ F O. Alternative activation of macrophages: mechanism and functions [J]. Immunity, 2010, 32(5): 593-604. |
| [21] | KAPLAN M H, SCHINDLER U, SMILEY S T, et al. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells [J]. Immunity, 1996, 4(3): 313-9. |
| [22] | WEI G, ABRAHAM B J, YAGI R, et al. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types [J]. Immunity, 2011, 35(2): 299-311. |
| [23] | ZHENG W, FLAVELL R A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells [J]. Cell, 1997, 89(4): 587-96. |
| [24] | OUYANG W, RANGANATH S H, WEINDEL K, et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism [J]. Immunity, 1998, 9(5): 745-55. |
| [25] | HWANG E S, SZABO S J, SCHWARTZBERG P L, et al. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3 [J]. Science, 2005, 307(5708): 430-3. |
| [26] | HUANG D, CHEN X, ZENG X, et al. Targeting regulator of G protein signaling 1 in tumor-specific T cells enhances their trafficking to breast cancer [J]. Nat Immunol, 2021, 22(7): 865-79. |
| [27] | PARK H, LI Z, YANG X O, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 [J]. Nat Immunol, 2005, 6(11): 1133-41. |
| [28] | LIANG S C, TAN X Y, LUXENBERG D P, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides [J]. J Exp Med, 2006, 203(10): 2271-9. |
| [29] | PATEL DHAVALKUMAR D, KUCHROO VIJAY K. Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic Interventions [J]. Immunity, 2015, 43(6): 1040-51. |
| [30] | IVANOV, II, MCKENZIE B S, ZHOU L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells [J]. Cell, 2006, 126(6): 1121-33. |
| [31] | BILATE A M, LAFAILLE J J. Induced CD4+Foxp3+ regulatory T cells in immune tolerance [J]. Annu Rev Immunol, 2012, 30: 733-58. |
| [32] | LIYANAGE U K, MOORE T T, JOO H G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma [J]. J Immunol, 2002, 169(5): 2756-61. |
| [33] | DAVIDSON T S, DIPAOLO R J, ANDERSSON J, et al. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells [J]. J Immunol, 2007, 178(7): 4022-6. |
| [34] | BURCHILL M A, YANG J, VOGTENHUBER C, et al. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells [J]. J Immunol, 2007, 178(1): 280-90. |
| [35] | FONTENOT J D, GAVIN M A, RUDENSKY A Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells [J]. Nat Immunol, 2003, 4(4): 330-6. |
| [36] | KIMURA A, KISHIMOTO T. IL-6: regulator of Treg/Th17 balance [J]. Eur J Immunol, 2010, 40(7): 1830-5. |
| [37] | LEE Y K, TURNER H, MAYNARD C L, et al. Late developmental plasticity in the T helper 17 lineage [J]. Immunity, 2009, 30(1): 92-107. |
| [38] | GAGLIANI N, AMEZCUA VESELY M C, ISEPPON A, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation [J]. Nature, 2015, 523(7559): 221-5. |
| [39] | JAROUŠEK R, MIKULOVá A, DAĎOVá P, et al. Single-cell RNA sequencing analysis of T helper cell differentiation and heterogeneity [J]. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2022, 1869(10). |
| [40] | KANNAGI M, HASEGAWA A, NAGANO Y, et al. Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL [J]. Retrovirology, 2019, 16(1): 23. |
| [41] | ZHAO T, MATSUOKA M. HBZ and its roles in HTLV-1 oncogenesis [J]. Front Microbiol, 2012, 3: 247. |
| [42] | YASUMA K, YASUNAGA J, TAKEMOTO K, et al. HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT) [J]. PLoS Pathog, 2016, 12(1): e1005372. |
| [43] | AGACE W W. Tissue-tropic effector T cells: generation and targeting opportunities [J]. Nat Rev Immunol, 2006, 6(9): 682-92. |
| [44] | SUGATA K, SATOU Y, YASUNAGA J, et al. HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines [J]. Blood, 2012, 119(2): 434-44. |
| [45] | SUBRAMANIAN K, DIERCKX T, KHOURI R, et al. Decreased RORC expression and downstream signaling in HTLV-1-associated adult T-cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy? [J]. Int J Cancer, 2019, 144(7): 1664-75. |
| [46] | PUZZOLO M C, DEL GIUDICE I, PERAGINE N, et al. TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia [J]. Front Oncol, 2021, 11: 637186. |
| [47] | SATOU Y, YASUNAGA J-I, ZHAO T, et al. HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo [J]. PLoS Pathog, 2011, 7(2): e1001274. |
| [48] | LUBAN J, YAMAMOTO-TAGUCHI N, SATOU Y, et al. HTLV-1 bZIP Factor Induces Inflammation through Labile Foxp3 Expression [J]. PLoS Pathog, 2013, 9(9). |
| [49] | GIAM C-Z, SEMMES O J. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ [J]. Viruses, 2016, 8(6): 161. |
| [50] | CURRER R, VAN DUYNE R, JAWORSKI E, et al. HTLV tax: a fascinating multifunctional co-regulator of viral and cellular pathways [J]. Front Microbiol, 2012, 3: 406. |
| [51] | KATAOKA K, NAGATA Y, KITANAKA A, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma [J]. Nature Genetics, 2015, 47(11): 1304-15. |
| [52] | MAHGOUB M, YASUNAGA J-I, IWAMI S, et al. Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells [J]. Proceedings of the National Academy of Sciences, 2018, 115(6): E1269-E78. |
| [53] | TANIGUCHI Y, NOSAKA K, YASUNAGA J, et al. Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms [J]. Retrovirology, 2005, 2: 64. |
| [54] | ARAYA N, SATO T, ANDO H, et al. HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells [J]. The Journal of Clinical Investigation, 2014, 124(8): 3431-42. |
| [55] | OTAGUIRI K K, DOS SANTOS D F, SLAVOV S N, et al. TAX-mRNA-Carrying Exosomes from Human T Cell Lymphotropic Virus Type 1-Infected Cells Can Induce Interferon-Gamma ProductionIn Vitro [J]. AIDS Res Hum Retroviruses, 2018, 34(12): 1075-82. |
| [56] | GILLI S C O, SALLES T S I, SAAD S T O. Regulation of the GATA3 promoter by human T‐cell lymphotropic virus type I Tax protein [J]. Journal of Cellular Biochemistry, 2004, 93(6): 1178-87. |
| [57] | DODON M D, LI Z, HAMAIA S, et al. Tax protein of human T-cell leukaemia virus type 1 induces interleukin 17 gene expression in T cells [J]. Journal of General Virology, 2004, 85(7): 1921-32. |
| [58] | HORIUCHI S, YAMAMOTO N, DEWAN M Z, et al. Human T-cell leukemia virus type-I Tax induces expression of interleukin-6 receptor (IL-6R): Shedding of soluble IL-6R and activation of STAT3 signaling [J]. Int J Cancer, 2006, 119(4): 823-30. |
| [59] | CROFT M, SO T, DUAN W, et al. The significance of OX40 and OX40L to T-cell biology and immune disease [J]. Immunol Rev, 2009, 229(1): 173-91. |
| [60] | BRITES C, GRASSI M F, QUARESMA J A S, et al. Pathogenesis of HTLV-1 infection and progression biomarkers: An overview [J]. The Brazilian Journal of Infectious Diseases, 2021, 25(3): 101594. |
| [61] | GRASSMANN R, ABOUD M, JEANG K T. Molecular mechanisms of cellular transformation by HTLV-1 Tax [J]. Oncogene, 2005, 24(39): 5976-85. |
| [62] | LI-WEBER M, GIAISI M, CHLICHLIA K, et al. Human T cell leukemia virus type I Tax enhances IL-4 gene expression in T cells [J]. European Journal of Immunology, 2001, 31(9): 2623-32. |
| [63] | MORI N, YAMASHITA U, TANAKA Y, et al. Interleukin-4 induces proliferation of adult T-cell leukemia cells [J]. Eur J Haematol, 1993, 50(3): 133-40. |
| [64] | SAWADA Y, NAKAMURA M, KABASHIMA-KUBO R, et al. Defective epidermal innate immunity and resultant superficial dermatophytosis in adult T-cell leukemia/lymphoma [J]. Clin Cancer Res, 2012, 18(14): 3772-9. |
| [65] | YAMAGISHI M, KUBOKAWA M, KUZE Y, et al. Chronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma [J]. Nat Commun, 2021, 12(1): 4821. |
| [66] | TAROKHIAN H, RAHIMI H, MOSAVAT A, et al. HTLV-1-host interactions on the development of adult T cell leukemia/lymphoma: virus and host gene expressions [J]. BMC Cancer, 2018, 18(1): 1287. |
| [67] | INAGAKI A, ISHIDA T, ISHII T, et al. Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: high interleukin-5 and -10 levels are significant unfavorable prognostic factors [J]. Int J Cancer, 2006, 118(12): 3054-61. |
| [68] | NOSAKA K, MATSUOKA M. Adult T-cell leukemia-lymphoma as a viral disease: Subtypes based on viral aspects [J]. Cancer Sci, 2021, 112(5): 1688-94. |
| [69] | SHAFFER A L, ROSENWALD A, HURT E M, et al. Signatures of the Immune Response [J]. Immunity, 2001, 15(3): 375-85. |
| [70] | CHUANG H-Y, LEE E, LIU Y-T, et al. Network-based classification of breast cancer metastasis [J]. Molecular Systems Biology, 2007, 3(1): 140. |
| [71] | ONO M, TANAKA R J, KANO M. Visualisation of the T cell differentiation programme by Canonical Correspondence Analysis of transcriptomes [J]. BMC Genomics, 2014, 15(1): 1028. |
| [72] | ONO M, TANAKA R J, KANO M, et al. Visualising the Cross-Level Relationships between Pathological and Physiological Processes and Gene Expression: Analyses of Haematological Diseases [J]. PLOS ONE, 2013, 8(1): e53544. |
| [73] | BRADLEY A, HASHIMOTO T, ONO M. Elucidating T Cell Activation-Dependent Mechanisms for Bifurcation of Regulatory and Effector T Cell Differentiation by Multidimensional and Single-Cell Analysis [J]. Frontiers in Immunology, 2018, 9. |
| [74] | TAN B J Y, SUGATA K, REDA O, et al. HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma [J]. Journal of Clinical Investigation, 2021, 131(24). |
