Expanded Human Blood-Derived Î³Î´T Cells Display Potent Antigen-Presentation Functions

Khan, Mohd Wajid Ali; Curbishley, Stuart M.; Chen, Hung-Chang; Thomas, Andrew D.; Pircher, Hanspeter; Mavilio, Domenico; Steven, Neil; Eberl, Matthias; Moser, Bernhard

doi:10.3389/fimmu.2014.00344

Cited by 38 publications

(54 citation statements)

References 65 publications

(81 reference statements)

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“…Importantly, only unconventional T cellprimed neutrophils, but not freshly isolated neutrophils, were also able to induce robust responses by M1(p58-66)-specific responder CD8 + T cells when utilizing the full-length M1 protein (Fig. 6A), a 251-aa-long Ag that requires uptake, processing, and loading of M1(p58-66) onto intracellular MHC class I molecules for crosspresentation to CD8 + T cells (36)(37)(38). Control experiments supported the need for Ag uptake and processing, as recombinant M1 protein could not be pulsed directly onto neutrophils, demonstrating the absence of potential degradation products in the M1 protein preparation that might be able to bind directly to cell surface-associated MHC class I molecules on neutrophils or CD8 + T cells (Fig.…”

Section: Unconventional T Cell-primed Neutrophils Cross-present Ags Tmentioning

confidence: 99%

“…For MHC class I-restricted Ag presentation, Ag-specific HLA-A2-restricted CD8 + T cell lines were generated using the immunodominant peptide of influenza matrix protein, M1(p58-66) (GILGFVFTL), as described before (37,38). M1(p58-66)-specific responder CD8 + T cells used in APC assays were .95% pure, as confirmed by tetramer staining (data not shown).…”

Section: Neutrophil Culturementioning

confidence: 99%

“…+ T cell responses, we assessed the potential of APC-like neutrophils to trigger CD8 + T cell responses, by taking advantage of HLA-A2-restricted responder T cell lines specific for M1(p58-66), the immunodominant epitope of the influenza M1 protein (36)(37)(38). Using the M1(p58-66) peptide, which can be pulsed readily onto cell surface-associated MHC class I molecules for direct presentation to CD8 + T cells, unconventional T cellprimed neutrophils showed a significantly improved Ag presentation, compared with freshly isolated neutrophils (Fig.…”

Section: Unconventional T Cell-primed Neutrophils Cross-present Ags Tmentioning

confidence: 99%

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Microbe-Specific Unconventional T Cells Induce Human Neutrophil Differentiation into Antigen Cross-Presenting Cells

Davey

Kift-Morgan

Liuzzi

et al. 2014

The Journal of Immunology

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The early immune response to microbes is dominated by the recruitment of neutrophils whose primary function is to clear invading pathogens. However, there is emerging evidence that neutrophils play additional effector and regulatory roles. The present study demonstrates that human neutrophils assume antigen cross-presenting functions, and suggests a plausible scenario for the local generation of APC-like neutrophils through the mobilization of unconventional T-cells in response to microbial metabolites. Vγ9/Vδ2 T-cells and MAIT cells are abundant in blood, inflamed tissues and mucosal barriers. Here, both human cell types responded rapidly to neutrophils after phagocytosis of Gram-positive and Gram-negative bacteria producing the corresponding ligands, and in turn mediated the differentiation of neutrophils into APCs for both CD4+ and CD8+ T-cells through secretion of GM-CSF, IFN-γ and TNF-α. In patients with acute sepsis, circulating neutrophils displayed a similar APC-like phenotype and readily processed soluble proteins for cross-presentation of antigenic peptides to CD8+ T-cells, at a time when peripheral Vγ9/Vδ2 T-cells were highly activated. Our findings indicate that unconventional T-cells represent key controllers of neutrophil-driven innate and adaptive responses to a broad range of pathogens.

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Section: Unconventional T Cell-primed Neutrophils Cross-present Ags Tmentioning

confidence: 99%

Section: Neutrophil Culturementioning

confidence: 99%

Section: Unconventional T Cell-primed Neutrophils Cross-present Ags Tmentioning

confidence: 99%

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Microbe-Specific Unconventional T Cells Induce Human Neutrophil Differentiation into Antigen Cross-Presenting Cells

Davey

Kift-Morgan

Liuzzi

et al. 2014

The Journal of Immunology

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“…Activated Vc9/ Vd2 T cells turned out to be well equipped cross-presenting APCs capable of processing not only defined proteins but also complex material such as cell debris and whole bacteria, and shuttle endocytosed antigens into the cytosol for degradation by the proteasome [118][119][120]. As Vc9/Vd2 T cells retain their cytolytic potential when they acquire APC functions [127], this unique combination of direct target cytotoxicity and APC machinery allows for scenarios in which Vc9/Vd2 T cells would lyse transformed, stressed or infected cells, and take up and process released proteins for presentation to both CD4 + and CD8 + T cells, with enormous implications for novel immunotherapies and vaccines [128][129][130][131][132]. In this context, Himoudi et al [130] proposed a role for opsonizing antibodies in the efficient 'licensing' of Vc9/Vd2 T-APCs, by enhancing uptake of antibody-bound material via Fc receptors like CD16, which is expressed by Vc9/Vd2 T cells under certain stimulation conditions and on distinct subsets [133,134].…”

mentioning

confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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“…Many laboratories have already demonstrated how easy it is to expand γδ T cells to very large numbers during in vitro culture ( 24 – 35 ). Based on these findings, we have developed a method for the generation of in vitro expanded γδT-APC that may provide the basis for their large-scale manufacture under clinical-grade conditions ( 36 ). In brief, best results, both in terms of yield and quality, are achieved when PBMC samples isolated from fresh blood are stimulated once with zoledronate and then cultured in the presence of the growth factors IL-2 and IL-15.…”

Section: Methods For the Generation Of Antigen-presenting γδT-apcmentioning

confidence: 99%

Potential Use of Î³Î´ T Cell-Based Vaccines in Cancer Immunotherapy

2014

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Immunotherapy is a fast advancing methodology involving one of two approaches: (1) compounds targeting immune checkpoints and (2) cellular immunomodulators. The latter approach is still largely experimental and features in vitro generated, live immune effector cells, or antigen-presenting cells. γδ T cells are known for their efficient in vitro tumor killing activities. Consequently, many laboratories worldwide are currently testing the tumor killing function of γδ T cells in clinical trials. Reported benefits are modest; however, these studies have demonstrated that large γδ T-cell infusions were well tolerated. Here, we discuss the potential of using human γδ T cells not as effector cells but as a novel cellular vaccine for treatment of cancer patients. Antigen-presenting γδ T cells do not require to home to tumor tissues but, instead, need to interact with endogenous, tumor-specific αβ T cells in secondary lymphoid tissues. Newly mobilized effector αβ T cells are then thought to overcome the immune blockade by creating proinflammatory conditions fit for effector T-cell homing to and killing of tumor cells. Immunotherapy may include tumor antigen-loaded γδ T cells alone or in combination with immune checkpoint inhibitors.

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Expanded Human Blood-Derived Î³Î´T Cells Display Potent Antigen-Presentation Functions

Cited by 38 publications

References 65 publications

Microbe-Specific Unconventional T Cells Induce Human Neutrophil Differentiation into Antigen Cross-Presenting Cells

Microbe-Specific Unconventional T Cells Induce Human Neutrophil Differentiation into Antigen Cross-Presenting Cells

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Potential Use of Î³Î´ T Cell-Based Vaccines in Cancer Immunotherapy

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