Antigens and Antigen-Presenting Molecules for γδ T Cells

Patients with relapsed or refractory acute myeloid leukemia (AML) are at increased risk of mortality. Higher γδ T cell count in a bone marrow or peripheral blood of patients with leukemia is associated with better survival. However, γδ T cells are rare in the blood and functionally impaired or exhausted in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and IL-2. Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K562 CD3/CD137L/CD28/IL15RA quadruplet artificial antigen presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a GMP-compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of co-culture with aAPC, the majority of which exhibited central (47%) and effector (43%) memory phenotypes. Additionally, >90% of the expanded γδ T cells expressed NKG2D, while they have low cell surface expression of PD1 and LAG2 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded, previously cryopreserved, γδ T cells were effective in killing target cells. Our results demonstrate that large scale ex vivo expansion of donor-derived γδ T cells can be achieved with the use of CD3/CD137L/CD28/IL15RA quadruplet aAPC and zol/IL-2 for clinical application as promising antineoplastic immunotherapy. Figure 1 Disclosures Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

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Interleukin 35: an overview

Polish Annals of Medicine ◽

10.29089/2020.20.00130 ◽

2020 ◽

Author(s):

Natalia Zdanowska ◽

Agnieszka Barbara Owczarczyk-Saczonek ◽

Wojciech Zdanowski ◽

Waldemar Juliusz Placek

Keyword(s):

T Cells ◽

Cardiovascular Diseases ◽

Cd8 T Cells ◽

Current Knowledge ◽

Γδ T Cells ◽

Immune Dysregulation ◽

Regulatory B Cells ◽

Forkhead Box ◽

Neurologic Disorders ◽

Antigen Presenting

Introduction: Interleukin 35 (IL-35) has recently been characterized as a cytokine connected with the IL-12 group. The secretion of IL-35 was described in forkhead box protein 3 (Foxp3) + regulatory T cells (Tregs), peripheral γδ T cells, CD8+ T cells, placental trophoblasts, antigen-presenting cells (APCs) and regulatory B cells (Breg). Aim: The aim of this paper is to systematize current knowledge about IL-35 production and discuss its impact on the pathophysiology and outcome of various diseases. Material and methods: Literature review was conducted. Results and discussion: IL-35 plays a pivotal role in the immune dysregulation in the pathogenesis of cardiovascular diseases including atherosclerosis, psychiatric and neurologic disorders, cancer, allergic and autoimmune diseases and psoriasis, inducing the expression of Treg-related cytokines and inhibiting the expression of Th1- and Th17-related cytokines.

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Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003339 ◽

2021 ◽

Vol 9 (12) ◽

pp. e003339

Author(s):

Huaishan Wang ◽

Hui Chen ◽

Shujing Liu ◽

Jie Zhang ◽

Hezhe Lu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Expansion ◽

Γδ T Cells ◽

Mtor Pathway ◽

Two Dimensional ◽

Γδ T Cell ◽

T Cell Expansion ◽

Antigen Presenting

BackgroundGamma delta (γδ) T cells are attractive effector cells for cancer immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive cell therapy. However, adoptive transfer of the expanded Vδ2 T cells has limited clinical efficacy.MethodsWe developed a costimulation method for expansion of Vδ2 T cells in PBMCs by activating γδ T-cell receptor (γδTCR) and Toll-like receptor (TLR) 7/8 using isopentenyl pyrophosphate (IPP) and resiquimod, respectively, and tested the functional markers and antitumoral effects in vitro two-dimensional two-dimensional and three-dimensional spheroid models and in vivo models. Single-cell sequencing dataset analysis and reverse-phase protein array were employed for mechanistic studies.ResultsWe find that Vδ2 T cells expanded by IPP plus resiquimod showed significantly increased cytotoxicity to tumor cells with lower programmed cell death protein 1 (PD-1) expression than Vδ2 T cells expanded by IPP or ZOL. Mechanistically, the costimulation enhanced the activation of the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (PKB/Akt)–the mammalian target of rapamycin (mTOR) pathway and the TLR7/8–MyD88 pathway. Resiquimod stimulated Vδ2 T-cell expansion in both antigen presenting cell dependent and independent manners. In addition, resiquimod decreased the number of adherent inhibitory antigen-presenting cells (APCs) and suppressed the inhibitory function of APCs by decreasing PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in these cells during in vitro Vδ2 T-cell expansion. Finally, we showed that human Vδ2 T cells can be expanded from PBMCs and spleen of humanized NSG mice using IPP plus resiquimod or ZOL, demonstrating that humanized mice are a promising preclinical model for studying human γδ T-cell development and function.ConclusionsVδ2 T cells expanded by IPP and resiquimod demonstrate improved anti-tumor function and have the potential to increase the efficacy of γδ T cell-based therapies.

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Impairment of antigen-presenting function of peripheral γδ T cells in patients with sepsis

Clinical & Experimental Immunology ◽

10.1093/cei/uxab029 ◽

2021 ◽

Author(s):

Xue-Wei Yang ◽

Hong Li ◽

Ting Feng ◽

Wei Zhang ◽

Xiang-Rong Song ◽

...

Keyword(s):

T Cells ◽

Fluorescent Protein ◽

Γδ T Cells ◽

In Vitro Study ◽

Healthy Individuals ◽

Γδt Cells ◽

Green Fluorescent ◽

Antigen Presenting ◽

Αβ T Cells

Abstract Impairment of antigen-presenting functions is a key mechanism contributing to sepsis-induced immunosuppression. Recently, γδ T cells have been demonstrated as professional antigen-presenting cells (APCs); however, their role in sepsis remains unknown. In this in vitro study, the APC function of human peripheral γδ T cells was assessed using samples collected from 42 patients with sepsis and 27 age-matched healthy controls. The APC-related markers HLA-DR, CD27, CD80, and CCR7 on fresh γδ T cells were significantly higher in patients with sepsis compared with matched controls; however, they responded poorly to 4-hydroxy-3-methyl-2-butenyl pyrophosphate (HMBPP) stimulation, characterised by the deactivation of these APC markers and impaired proliferation. Furthermore, the adhesion function of γδ T cells, essential for antigen presentation, was greatly reduced in patients with sepsis; for instance, in co-cultures with green fluorescent protein-expressing Escherichia coli, HMBPP-activated γδT cells from healthy individuals adhered to E. coli efficiently, whereas no such phenomenon was observed with respect to γδT cells from patients with sepsis. In line with these results, in co-cultures with isolated CD4 + αβ T cells, HMBPP-activated γδT cells of healthy individuals promoted the efficient proliferation of CD4 + αβ T cells, whereas γδT cells from patients with sepsis did not do so. In conclusion, our findings show that the antigen-presenting function of γδ T cells is severely impaired in patients with sepsis and the mechanisms behind need further study.

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A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1

Science ◽

10.1126/science.aav3900 ◽

2019 ◽

Vol 366 (6472) ◽

pp. 1522-1527 ◽

Cited By ~ 37

Author(s):

Jérôme Le Nours ◽

Nicholas A. Gherardin ◽

Sri H. Ramarathinam ◽

Wael Awad ◽

Florian Wiede ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Γδ T Cells ◽

Mhc I ◽

Cell Receptors ◽

Histocompatibility Complex ◽

Antigen Complex ◽

Binding Cleft ◽

Antigen Presenting

T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I–like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR–MR1–antigen complex starkly contrasts with all other TCR–MHC and TCR–MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.

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Mouse γδ T cells are capable of expressing MHC class II molecules, and of functioning as antigen-presenting cells

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2008.06.007 ◽

2008 ◽

Vol 203 (1) ◽

pp. 3-11 ◽

Cited By ~ 66

Author(s):

Lan Cheng ◽

Yan Cui ◽

Hui Shao ◽

Gencheng Han ◽

Ling Zhu ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Γδ T Cells ◽

Antigen Presenting Cells ◽

Class Ii ◽

Antigen Presenting ◽

Mhc Class Ii Molecules

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Myeloid molecular characteristics of human γδ T cells support their acquisition of tumor antigen-presenting capacity

Cancer Immunology Immunotherapy ◽

10.1007/s00262-015-1700-x ◽

2015 ◽

Vol 64 (8) ◽

pp. 941-949 ◽

Cited By ~ 15

Author(s):

Masato Muto ◽

Muhammad Baghdadi ◽

Ryuji Maekawa ◽

Haruka Wada ◽

Ken-ichiro Seino

Keyword(s):

T Cells ◽

Tumor Antigen ◽

Γδ T Cells ◽

Molecular Characteristics ◽

Antigen Presenting

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Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease

Journal of Experimental Medicine ◽

10.1084/jem.20120707 ◽

2013 ◽

Vol 210 (9) ◽

pp. 1675-1684 ◽

Cited By ~ 50

Author(s):

Céline Molle ◽

Tong Zhang ◽

Laure Ysebrant de Lendonck ◽

Cyril Gueydan ◽

Mathieu Andrianne ◽

...

Keyword(s):

T Cells ◽

Mrna Stability ◽

Γδ T Cells ◽

Skin Lesions ◽

Strong Impact ◽

Immunological Parameters ◽

Draining Lymph Node ◽

Interleukin 23 ◽

Antigen Presenting ◽

Inflammatory Syndrome

Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine–rich element (ARE)–binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow–derived dendritic cells (BMDCs) from TTP−/− mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3′ untranslated region. TTP−/− mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23–IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation.

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