Antigen-Specific Inhibition of High-Avidity T Cell Target Lysis by Low-Avidity T Cells via Trogocytosis

Chung, Brile; Stuge, Tor B.; Murad, John P.; Beilhack, Georg F.; Andersen, Emily S.; Armstrong, Brian; Weber, Jeffrey S.; Lee, Peter P.

doi:10.1016/j.celrep.2014.06.052

Cited by 22 publications

(23 citation statements)

References 25 publications

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“…Thus, the donor cells seem to retain a sufficient amount of MHCI on their cell surface even after the transfer. However, interestingly, Chung et al recently reported that low-avidity CTLs strip MHCI off target tumor cells via the mechanism of trogocytosis without killing, resulting in an interference with high-avidity CTLs in tumor lysis ( 8 ). It remains unknown whether donor DCs lose the antigen-presenting activity after the release of their MHC molecules to recipient DCs.…”

Section: Antigen Presentation By Mhci-dressed Cells: Cross-dressingmentioning

confidence: 99%

“…In this study, mouse T cells were adoptively transferred to MHC-mismatched mice, and the authors surprisingly found the MHC of the recipient mice on transferred T cells ( 1 ). Since this seminal study, numerous others have shown that the T cell receptor (TCR) rapidly (within minutes) acquires MHC molecules from antigen-presenting cells (APCs) via the immunological synapse formed at cell–cell contact area, and that this phenomenon impacts T cell activation ( 2 – 8 ), although the physiological relevance of this is still not fully understood. This intercellular transfer of plasma membrane has been called absorption, acquisition, nibbling, shaving, snatching, stripping, or trogocytosis, which is from the ancient Greek Trogo , meaning “gnaw” ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Antigen Presentation by MHC-Dressed Cells

Nakayama

2015

Front. Immunol.

105

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Professional antigen-presenting cells (APCs) such as conventional dendritic cells (DCs) process protein antigens to MHC-bound peptides and then present the peptide–MHC complexes to T cells. In addition to this canonical antigen presentation pathway, recent studies have revealed that DCs and non-APCs can acquire MHC class I (MHCI) and/or MHC class II (MHCII) from neighboring cells through a process of cell–cell contact-dependent membrane transfer called trogocytosis. These MHC-dressed cells subsequently activate or regulate T cells via the preformed antigen peptide–MHC complexes without requiring any further processing. In addition to trogocytosis, intercellular transfer of MHCI and MHCII can be mediated by secretion of membrane vesicles such as exosomes from APCs, generating MHC-dressed cells. This review focuses on the physiological role of antigen presentation by MHCI- or MHCII-dressed cells, and also discusses differences and similarities between trogocytosis and exosome-mediated transfer of MHC.

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Section: Antigen Presentation By Mhci-dressed Cells: Cross-dressingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antigen Presentation by MHC-Dressed Cells

Nakayama

2015

Front. Immunol.

105

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“…Therapeutic peptide vaccines can robustly induce a tumor-specific CTL response with limited side effects due to induction of an antigen-specific immune response rather than broad immune activation (18). Preferential development of high avidity anti-tumor CTLs enables enhanced tumor cell killing (8,16). Previously, we showed that vaccine dosages could be optimized to preferentially elicit highavidity CTLs, unlike standard dosages that elicit low-avidity CTLs (14).…”

Section: Discussionmentioning

confidence: 99%

“…We previously developed a mathematical model to study how vaccine-induced avidity selection affects tumor clearance (14). This model was calibrated to ex vivo human data from Chung et al (16) and then validated against data from (17,18). Here, we extend this model to show that induction of immature DCs may improve current treatments by eliciting high-avidity CTLs.…”

Section: Methodsmentioning

confidence: 97%

Immature dendritic cells promote high-avidity tuning of vaccine T cell response

Kumbhari

Egelston

Lee

et al. 2020

Preprint

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Therapeutic vaccines can elicit tumor-specific cytotoxic T lymphocytes (CTLs), but durable reductions in tumor burden require vaccines that stimulate high-avidity CTLs. Recent advances in immunotherapy responses have led to renewed interest in vaccine approaches, including dendritic cell vaccine strategies. However, dendritic cell requirements for vaccines that generate potent anti-tumor T-cell responses are unclear. Here we use mathematical modeling to show that counterintuitively, increasing levels of immature dendritic cells may lead to selective expansion of high-avidity CTLs. This finding contrasts with traditional dendritic cell vaccine approaches that have sought to harness ex vivo generated mature dendritic cells. We show that the injection of vaccine antigens in the context of increased numbers of immature dendritic cells results in a decreased overall peptide:MHC complex load that favors high-avidity CTL activation and expansion. Overall, our results provide a firm basis for further development of this approach, both alone and in combination with other immunotherapies such as checkpoint blockade.

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“…Only recently has the phenomenon of uptake of pMHC molecules from tumor cell membrane by CTLs via trogocytosis been acknowledged [ 36 ]. The emphasis, however, was on the effect of depletion of pMHCs from the tumor surface, snatched by low avidity CTLs, leading to insufficient triggering of high-avidity CTLs and diminished melanoma lysis.…”

Section: Discussionmentioning

confidence: 99%

Human T Cell Crosstalk Is Induced by Tumor Membrane Transfer

et al. 2015

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Trogocytosis is a contact-dependent unidirectional transfer of membrane fragments between immune effector cells and their targets, initially detected in T cells following interaction with professional antigen presenting cells (APC). Previously, we have demonstrated that trogocytosis also takes place between melanoma-specific cytotoxic T lymphocytes (CTLs) and their cognate tumors. In the present study, we took this finding a step further, focusing on the ability of melanoma membrane-imprinted CD8+ T cells to act as APCs (CD8+T-APCs). We demonstrate that, following trogocytosis, CD8+T-APCs directly present a variety of melanoma derived peptides to fraternal T cells with the same TCR specificity or to T cells with different TCRs. The resulting T cell-T cell immune synapse leads to (1) Activation of effector CTLs, as determined by proliferation, cytokine secretion and degranulation; (2) Fratricide (killing) of CD8+T-APCs by the activated CTLs. Thus, trogocytosis enables cross-reactivity among CD8+ T cells with interchanging roles of effectors and APCs. This dual function of tumor-reactive CTLs may hint at their ability to amplify or restrict reactivity against the tumor and participate in modulation of the anti-cancer immune response.

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Antigen-Specific Inhibition of High-Avidity T Cell Target Lysis by Low-Avidity T Cells via Trogocytosis

Cited by 22 publications

References 25 publications

Antigen Presentation by MHC-Dressed Cells

Antigen Presentation by MHC-Dressed Cells

Immature dendritic cells promote high-avidity tuning of vaccine T cell response

Human T Cell Crosstalk Is Induced by Tumor Membrane Transfer

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