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Human Γδt-Cell Subsets and Their Involvement in Tumor Immunity

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Human Γδt-Cell Subsets and Their Involvement in Tumor Immunity OPEN Cellular & Molecular Immunology (2017) 14, 245–253 www.nature.com/cmi REVIEW Human γδT-cell subsets and their involvement in tumor immunity Dang Wu1,2,6, Pin Wu2,3,6, Fuming Qiu2,4, Qichun Wei1,2 and Jian Huang2,5 γδT cells are a conserved population of innate lymphocytes with diverse structural and functional heterogeneity that participate in various immune responses during tumor progression. γδT cells perform potent immunosurveillance by exerting direct cytotoxicity, strong cytokine production and indirect antitumor immune responses. However, certain γδT-cell subsets also contribute to tumor progression by facilitating cancer-related inflammation and immunosuppression. Here, we review recent observations regarding the antitumor and protumor roles of major structural and functional subsets of human γδT cells, describing how these subsets are activated and polarized, and how these events relate to subsequent function in tumor immunity. These studies provide insights into the manipulation of γδT-cell function to facilitate more targeted approaches for tumor therapy. Cellular & Molecular Immunology (2017) 14, 245–253; doi:10.1038/cmi.2016.55; published online 28 November 2016 Keywords: antitumor; γδT cells; protumor; subsets; tumor immunity INTRODUCTION γδT cells in adoptive cell therapy.7 However, human γδT cells γδT cells, which are innate-like T lymphocytes characterized by have diverse physiological roles in tumor immunity, owing to T-cell receptors (TCRs) composed of γ and δ chains, are widely their wide-ranging structural subsets, which are defined distributed in the peripheral blood (PB) and mucosal tissues.1 by their TCR repertoire and functional heterogeneity driven γδT cells rapidly recognize exogenous pathogens and endo- by differential environmental stimulation.8,9 Recent reports genous stress-induced ligands in a major histocompatibility have described the diverse responses of human γδTcellsto complex (MHC)-unrestricted manner and initiate adaptive tumors.10 For example, γδT cells exert cytotoxicity toward immunity, acting as a first line of immune defense.2 Activated tumor cells via the NKG2D pathway;11 however, they also γδT cells exhibit multiple effector functions, including cyto- develop a regulatory profile by expressing interleukin-10 toxicity against infected or tumor cells, cytokine and chemo- (IL-10) and tumor growth factor (TGF)-β, thereby exerting kine production, antigen-presenting functions and regulatory suppressive effects on antitumor responses.12 Moreover, our abilities,3 thus allowing them to participate in an array of previous studies have indicated that human PB Vδ1Tcells diseases, including infection, allergy, autoimmunity and demonstrate favorable cytotoxicity against colon cancer,13 cancer.4–6 whereas γδT17 cells with Vδ1 TCR usage in colon cancer Human γδT cells contribute to the immune response against tissue promote tumor progression.14 a subset of tumors of hematological and epithelial origin, and Therefore, understanding γδT-cell subset-specific responses many clinical trials have been conducted to test the use of during tumor immunity is vital to rationally exploit the 1Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; 2Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education; Provincial Key Laboratory of Molecular Biology in Medical Sciences), Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; 3Department of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China; 4Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China and 5Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China 6These authors contributed equally to this work. Correspondence: Professor J Huang, MD, PhD, Department of Surgical Oncology, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Jiefang Road No. 88, Hangzhou 310009, China. E-mail: [email protected] or Professor QC Wei, MD, PhD, Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Jiefang Road No. 88, Hangzhou 310009, China. E-mail: [email protected] Received: 15 June 2016; Revised: 22 August 2016; Accepted: 23 August 2016 TheresponseofγδT-cell subsets to tumors DWuet al 246 antitumor activity of γδT cells while avoiding their tumor- cytotoxic effects.31 Vγ9Vδ2 T cells also respond to super- promoting effects during tumor therapy. In this review, we antigens such as staphylococcal enterotoxins (SEs) and toxic summarize research progress regarding the major structural shock syndrome toxin (TSST)-1.32,33 The above evidence has and functional subsets of human γδT cells and their effects on demonstrated that Vγ9Vδ2 T cells respond to a variety of tumor immunity, and we describe the clinical implications for ligands, although these represent only a few defined antigens; tumor therapy involving the manipulation of γδT-cell function. these responses suggest implications for the clinical manage- ment of these cells. STRUCTURAL SUBSETS AND γδT-CELL ACTIVATION Generally, human γδT cells are divided into two major Vδ1 γδTCELLS structural subsets according to their TCR δ chain usage: Vδ1 Vδ1 TCR gene rearrangement occurs 4–6 months after birth and Vδ2Tcells.15 In terms of TCR γ chain usage, Vδ1Tcells and involves the joining of Vδ1toDδ1orDδ2 and the joining are predominantly associated with the VγI gene family (Vγ2/3/ of upstream Vγ gene segments, including Vγ2, 3, 5 and 8, to 4/5/8), whereas the majority of Vδ2 T cells coexpress VγII Jγ2.19 Unlike Vγ9Vδ2 T cells, human Vδ1Tcellsprimarily (Vγ9).16 γδT subsets exhibit distinct developmental properties, reside in the gut epithelia, dermis, spleen and liver, and are tissue localization and activation modes.1,17,18 involved in maintaining epithelial tissue integrity.1 Vδ1 T cells constitute less than 30% of γδT cells in PB and contain diverse Vγ9Vδ2 γδT CELLS paired Vγ chains.15,16 During HIV infection, Vδ1 T-cell γδT-cell development primarily occurs in the fetal thymus, and numbers are increased, and the normal ratio of Vδ2/Vδ1 subsets arise through rearrangements at distinct phases of T cells is inverted, thus suggesting the potential involvement of thymic ontogeny.19 Vδ2 subsets are generated in the thymi at Vδ1 T cells in antiviral immunity.34 Ligand recognition by Vδ1 8.5–15 weeks in human embryos, with gene rearrangements of T cells remains largely uncharacterized, although CD1 family Vδ2toDδ3 and of Vγ1.8 or Vγ9toJγ1.19 Human Vδ2 T cells, proteins are recognized by Vδ1 T cells. Both PB and tissue Vδ1 which are almost exclusively paired with the Vγ9 chain (also T cells recognize CD1c35–37 and the lipid-presenting MHC-like termed Vγ9Vδ2 γδT cells), are predominant in the PB molecule CD1d via the TCR.38 Two recent studies have (470%),15 and are uniquely activated by phosphoantigens explored the structural basis of the recognition of lipid antigens produced by microbes and transformed cells. Exposure to (E)- by the Vδ1 TCR via CD1d-presenting molecules.39,40 In 4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), an addition to the CD1 family, human intestinal epithelial Vδ1 intermediate metabolite of microbial isoprenoid biosynthesis20 T cells respond to stress-induced MICA/B through the and Isopentenyl pyrophosphate (IPP), which is generated by synergistic actions of TCR and NKG2D.41,42 Specifically, in a transformed mammalian cells via the the mevalonate pathway, manner analogous to Vγ9Vδ2Tcells,Vδ1 T cells respond to leads to TCR-dependent activation of Vγ9Vδ2 T cells,21 thus tumor cells by overexpressing MICA/B and ULBPs via enabling them to rapidly respond to exogenous infection or NKG2D.43,44 Moreover, Vδ1Tcellsareactivatedbythe endogenous transformed cells. Moreover, aminobisphospho- superantigen SE but respond exclusively to SEB rather than nates such as zoledronic acid combined with low-dose IL-2 SEA.45 A unique feature of Vδ1 T-cell activation is the selectively activate and expand Vγ9Vδ2 T cells in vitro.22 recognition of B7-H6, a B7 family member exclusively Phosphoantigens interact with specific proteins rather than expressed on tumor cells, by NKp30, thereby exerting anti- being directly recognized by the TCR.23 F1-ATPase expressed tumor effects.46,47 on tumor cells has been defined as an antigen-recognition molecule for phosphoantigen-mediated stimulation of human NON-Vδ1 AND NON-Vγ9Vδ2 γδTCELLS Vγ9Vδ2 T cells.24 Butyrophilin3A1 is another essential phos- Human Vδ3 T cells compose the majority of non-Vδ1and phorylated antigen-presenting modality of Vγ9Vδ2T-cell non-Vγ9Vδ2 γδT cells and are found in healthy PB, the liver48 – activation.25 27 In addition to phosphoantigens, human MutS and in patients with cytomegalovirus (CMV) infection,49 HIV homolog 2, a DNA repair-related protein ectopically expressed infection50 and B-cell leukemia.51 Vδ3 T cells, paired with on tumor cells, is recognized by Vγ9Vδ2 T cells via the TCR.28 Vγ2orVγ3,50 respond to CD1d and express the degranulation Toll-like receptors (TLRs) and natural killer receptors marker CD107a.52 AVγ4Vδ5+ T-cell clone has been reported (NKRs) have been reported to co-stimulate human
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