Intercellular Trogocytosis Plays an Important Role in Modulation of Immune Responses

Ahmed, Khawaja Ashfaque; Munegowda, Manjunatha Ankathatti; Xie, Yufeng; Xiang, Jim

doi:10.1038/cmi.2008.32

Cited by 101 publications

(103 citation statements)

References 108 publications

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“…In contrast, the actin filament inhibitor, cytochalasin B, decreased the acquisition of CD1d by activated Vg9Vd2-T cells, suggesting that actin cytoskeleton rearrangement processes contribute to the observed exchange of membrane fragments. Polarization of the TCR (Vd2) at the site of CD1d-positive membrane exchange suggests that trogocytosis took place at the immunologic synapse, as reported previously (22,23).…”

Section: Discussionmentioning

confidence: 65%

“…3C. However, when quantified as a function of area and intensity, the CD1d staining on the plasma membrane of Vg9Vd2-T cells cultured with pAg þ HeLa-CD1d was larger and brighter than the CD1d staining on the plasma membrane of Vg9Vd2-T cells cultured with HeLa-CD1d ($2-fold increase; data not shown) and the percentage of Vg9Vd2-T cells that acquire CD1d after 4A and B), suggesting that the observed trogocytosis took place at an immunologic synapse, as described previously for trogocytosis (21)(22)(23).…”

Section: A-galcer-pulsed Pag-activated Vg9vd2-t Cells Do Not Triggermentioning

confidence: 99%

“…Trogocytosis is the process whereby lymphocytes intimately interact with other cells to extract surface molecules from these cells and present them on their own surface (21). The formation of an immune synapse through cell surface ligand-receptor interaction enables the rapid transfer of immunomodulatory surface proteins contained in a membrane patch, a process referred to as synaptic transfer (22,23). To evaluate whether membrane transfer between …”

Section: A-galcer-pulsed Pag-activated Vg9vd2-t Cells Do Not Triggermentioning

confidence: 99%

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CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Schneiders¹,

Prodöhl²,

Ruben³

et al. 2014

Cancer Immunology Research

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CD1d-restricted invariant natural killer T cells (iNKT) constitute an important immunoregulatory T-cell subset that can be activated by the synthetic glycolipid a-galactosylceramide (a-GalCer) and play a dominant role in antitumor immunity. Clinical trials with a-GalCer-pulsed monocyte-derived dendritic cells (moDC) have shown anecdotal antitumor activity in advanced cancer. It was reported that phosphoantigen (pAg)-activated Vg9Vd2-T cells can acquire characteristics of professional antigen-presenting cells (APC). Considering the clinical immunotherapeutic applications, Vg9Vd2-T APC can offer important advantages over moDC, potentially constituting an attractive novel APC platform. Here, we demonstrate that Vg9Vd2-T APC can present antigens to iNKT. However, this does not result from de novo synthesis of CD1d by Vg9Vd2-T, but critically depends on trogocytosis of CD1d-containing membrane fragments from pAg-expressing cells. CD1d-expressing Vg9Vd2-T cells were able to activate iNKT in a CD1d-restricted and a-GalCer-dependent fashion. Although a-GalCerloaded moDC outperformed Vg9Vd2-T APC on a per cell basis, Vg9Vd2-T APC possess unique features with respect to clinical immunotherapeutic application that make them an interesting platform for consideration in future clinical trials. Cancer Immunol Res; 2(8); 732-40. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 65%

Section: A-galcer-pulsed Pag-activated Vg9vd2-t Cells Do Not Triggermentioning

confidence: 99%

Section: A-galcer-pulsed Pag-activated Vg9vd2-t Cells Do Not Triggermentioning

confidence: 99%

See 1 more Smart Citation

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Schneiders¹,

Prodöhl²,

Ruben³

et al. 2014

Cancer Immunology Research

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“…Here, we show for the first time transfer of membrane proteins by trogocytosis (32,33) between target and T cells through immunologic synapses induced by a bsAb. Furthermore, we demonstrate that IFNa enhanced the therapeutic efficacy of (E1)-3s without increasing the production of other cytokines to levels that could induce cytokine release syndrome (CRS).…”

Section: Introductionmentioning

confidence: 99%

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

Rossi

Chang

et al. 2014

Molecular Cancer Therapeutics

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Trop-2 has limited presence on normal tissues but is highly expressed in diverse epithelial cancers. (E1)-3s is a T-cell-redirecting trivalent bispecific antibody (bsAb), comprising an anti-CD3 scFv covalently linked to a stabilized dimer of a Trop-2-targeting Fab using Dock-and-Lock. We show for the first time that bsAbmediated bidirectional trogocytosis occurs between target and T cells and involves immunologic synapses. We studied the effects of interferon-a (INFa) on (E1)-3s-mediated T-cell killing of human gastric and pancreatic cancer cell lines. T-cell activation, cytokine induction, and cytotoxicity were evaluated ex vivo using peripheral blood mononuclear cells (PBMC) or T cells with NCI-N87 gastric cancer as target cells. In vivo activity was assayed with NCI-N87 and Capan-1 (pancreatic) xenografts. In the presence of target cells and PBMCs, (E1)-3s did not cause excess cytokine production. When combined with (E1)-3s, peginterferonalfa-2a-which alone did not increase T-cell activation or raise cytokine levels over baseline-increased CD69 expression but did not significantly increase cytokine induction. (E1) 3s mediated a highly potent T-cell lysis of NCI-N87 target cells in vitro. Inclusion of peginterferonalfa-2a or a more potent form of INFa, 20 Ã -2b, significantly potentiated the activity of (E1)-3s by more than 2.5-or 7-fold, respectively. In vivo, combining peginterferonalfa-2a with (E1)-3s delayed Capan-1 growth longer than each single agent. Similarly, combination therapy delayed tumor proliferation of NCI-N87 compared with (E1)-3s or peginterferonalfa-2a single-treatment groups. (E1)-3s effectively induced T-cell-mediated killing of Trop-2-expressing pancreatic and gastric cancers, which was enhanced with INFa.

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“…30 Another potential mechanism for trogocytosis is via exosome fusion to acceptor cells or internalization and recycling of exosomal molecules on the acceptor cells. 31 The exosomal molecules on acceptor cells are quite stable and can last as long as 12 days in culture. 32 Activated T cells can also secrete bioactive EXO, [8][9][10] which can be taken up by DCs or B cells via direct intercellular molecule transfer from T cells to APCs.…”

Section: Discussionmentioning

confidence: 99%

CD4+ T cell-released exosomes inhibit CD8+ cytotoxic T-lymphocyte responses and antitumor immunity

et al. 2010

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T cells secrete bioactive exosomes (EXO), but the potential immunoregulatory effect of T-cell EXO is largely unknown. In this study, we generated activated ovalbumin (OVA)-specific CD4 1 T cells in vitro via coculture of OVA-pulsed dendritic cells (DC OVA ) with naive CD4 1 T cells derived from OVA-specific T-cell receptor (TCR) transgenic OTII mice. CD4 1 T-cell EXO were then purified from the CD4 1 T-cell culture supernatants by differential ultracentrifugation. CD41 T-cell EXO exhibited the 'saucer' shape that is characteristic of EXO with a diameter between 50 and 100 nm, as assessed by electron microscopy, and contained the EXO-associated proteins LAMP-1, TCR and lymphocyte function associated antigen-1 (LFA-1), as determined by western blot. Flow cytometric analysis showed that CD4 1 T-cell EXO expressed CD41 T-cell markers (CD4, TCR, LFA-1, CD25 and Fas ligand), but to a lesser extent than CD4 1 T cells. We demonstrated that DC OVA took up CD4 1 T-cell EXO via peptide/major histocompatibility complex (pMHC) II/TCR and CD54/LFA-1 interactions. OVA-specific CD41 T-cell EXO from OTII mice, but not ConA-stimulated polyclonal CD4 1 T-cell EXO from wild-type C57BL/6 mice inhibited DC OVA -stimulated in vitro CD4 1 T-cell proliferation and in vivo CD8 1 cytotoxic T lymphocyte (CTL) responses and antitumor immunity against OVA-expressing B16 melanoma BL6-10 OVA cells. In addition, EXO derived from a T-cell hybridoma cell line, MF72.2D9, expressing an OVA-specific CD4 1 TCR, had a similar inhibitory effect as OTII CD4 1 T-cell EXO on CTL-mediated antitumor immunity. Taken together, our data indicate that antigen-specific T-cell EXO may serve as a new type of immunosuppressive reagent for use in transplant rejection and treatment of autoimmune diseases.

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Intercellular Trogocytosis Plays an Important Role in Modulation of Immune Responses

Cited by 101 publications

References 108 publications

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

CD4+ T cell-released exosomes inhibit CD8+ cytotoxic T-lymphocyte responses and antitumor immunity

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