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Trogocytosis in T cell priming and effector phases. During the priming phase, dendritic cell (DC) type 2 cells (DC2s) present extracellular tumor antigens on MHCII to activate CD4 + T cells whereas DC type 1 cells (DC1s) are able to present them on MHCI, called cross-presentation, to activate CD8 + T cells. In addition, DC1s and/or DC2s acquire preformed antigen-MHCI complexes for antigen presentation to CD8 + T cells, which is called cross-dressing. In the cytotoxic T lymphocyte (CTL) effector phase, CTLs strip off target antigens from tumor cells. These CTLs with acquired tumor antigen-MHCI are then lysed by tumor-unexperienced CTLs through a process called fratricide cell death. On the other hand, tumor cells lose antigens, resulting in generation of CTL escape variants.
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Trogocytosis is an active process whereby plasma membrane proteins are transferred from one cell to the other cell in a cell-cell contact-dependent manner. Since the discovery of the intercellular transfer of major histocompatibility complex (MHC) molecules in the 1970s, trogocytosis of MHC molecules between various immune cells has been frequently...
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Context 1
... cDCs are further subdivided into DC type 1 cells (DC1s) and DC type 2 cells (DC2s) [41]. DC2s present extracellular antigens on MHCII through the conventional antigen presentation pathway whereas cDC1s are able to present extracellular antigens not only on MHCII, but also on MHCI, called cross-presentation ( Figure 2) [39][40][41]. In general, as observed in DC2s, extracellular antigens are processed and loaded on MHCII in phagosomes. ...
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... addition to the cross-presentation pathway, several recent studies have reported the cross-dressing pathway, in which DCs acquire MHCI molecules from neighboring DCs or tumor cells (Figure 2). These MHCI-dressed (cross-dressed) DCs activate CD8 + T cells via the preformed antigen peptide-MHCI complexes without the above-mentioned antigen processing [3,49,50]. ...
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... is also frequently observed in the CTL effector phase. When CTLs attack tumor cells, they acquire MHCI from tumor cells (Figure 2) [7,65]. However, it is still under debate whether trogocytosis enhances or suppresses CTL activity. ...
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... contrast, a regulatory function of the MHC on CTLs has been also reported. For instance, CTLs that have acquired the tumor antigen-MHC complex are recognized and lysed by tumor-unexperienced CTLs, which is called fratricide cell death (Figure 2) [7,65,71]. Likewise, it was recently reported that trogocytosis-mediated fratricide of chimeric antigen receptor (CAR) T cells causes tumor escape [72] (see Section 3.3). ...
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... is noteworthy that TCR-mediated trogocytosis strips tumor antigens from target tumor cells, causing antigen loss and tumor escape (Figure 2) [2,72,73]. For example, lowavidity CTLs remove tumor antigen-MHCI complexes from target tumor cells without killing, interfering with tumor killing by high-avidity CTLs [73]. ...
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Citations
... Trogocytosis is a process where two cells interact and exchange surface plasma membrane fragments, potentially transferring functional properties from one cell to another (29,30). In the case of T-and B-cell trogocytosis, a T cell interacts with a B cell through TCR:MHC binding, actively inducing the transfer of various surface proteins from the B cell to the T cell (30)(31)(32). If CD20 + T cells in humans, like in rodents, exclusively are a result of trogocytosis, it would impact a possible therapeutic approach where CD20 expression or a certain level of CD20 is a prerequisite for successful therapy. ...
... Following TCR:MHC-interaction between a T cell and a B cell, MHC can be transferred to the recipient T cell along with B-cell membrane fractions, including other B-cell surface molecules (30,34,35). Donor-derived proteins likely retain their biological function when transferred to the surface of the recipient cell; the recipient cell hereby gains novel functions, and in certain cases the donor cell loses function or even dies (30,32). Studies of both humans and rodents have indicated that T cells expressing CD20 possess a particular proinflammatory phenotype (1, 17); however, whether CD20 expressed on T cells is acquired through trogocytosis or is an intrinsic property of the T cell is highly debated. ...
Human T cells expressing CD20 play an important role in the defense against virus and cancer and are central in the pathogenesis of both malignancies and various autoimmune disorders. Therapeutic modulation of CD20⁺ T cells and the CD20 expression level is therefore of significant interest. In rodents, CD20 on T cells is likely the product of an active transfer of CD20 from a donor B cell interacting with a recipient T cell in a process termed trogocytosis. Whether the same applies to human CD20⁺ T cells is highly debated. Investigating this dispute showed that human CD20⁻ T cells could achieve CD20 along with a series of other B-cell markers from B cells through trogocytosis. However, none of these B-cell markers were co-expressed with CD20 on human CD20⁺ T cells in blood or inflamed CSF, implying that additional mechanisms may be involved in the development of human CD20⁺ T cells. In support of this, we identified true naïve CD20⁺ T cells, measured endogenous production of CD20, and observed that CD20 could be inherited to daughter cells, contradicting that all human CD20⁺ T cells are a product of trogocytosis.
... Although immune checkpoint therapy fundamentally reverses immune suppression within TME, tumor immunity also relies on tumor cells or antigen-presenting cells (APCs) activating CD8 + T cells through MHCI-TCR interactions 54 . A crucial step in this process involves the ubiquitination of abnormal antigens generated by tumor cell mutations, followed by their recombination within the endoplasmic reticulum to form MHCI-antigen peptide complexes. ...
Lymphocyte activating gene-3 (LAG3) is a distinctive T cell co-receptor that is expressed on the surface of lymphocytes. It plays a special inhibitory immune checkpoint role due to its unique domain and signaling pattern. Our aim is to explore the correlation between LAG3 in cancers and physiological processes related to a range of cancers, as well as build LAG3-related immunity and prognostic models. By comprehensively using of datasets and methods from TCGA, GTE-x and GEO databases, cBioPortal, HPA, Kaplan-Meier Plotter, Spearman, CellMinerTM, we delved deeper into the potential impact of the LAG3 in cancer development. These include expression differences, Localization of tumor cell subsets, immune infiltration, matrix infiltration, gene mutations, DNA methylation, signaling pathways and prognosis. Furthermore, we explored LAG3 interactions with different drugs. LAG3 is highly expressed in ACC (p < 0.001), BRCA (p < 0.001), DLBC (p < 0.001), ESCA (p < 0.001), GBM (p < 0.001), HNSC (p < 0.001), KIRC (p < 0.001), LGG (p < 0.001), LUAD (p < 0.01), LUSC (p < 0.001), PAAD (p < 0.001), PCPG (p < 0.01), SKCM (p < 0.001), STAD (p < 0.001), TGCT (p < 0.001) and THCA (p < 0.05), while lowly expressed in COAD (p < 0.001), LIHC (p < 0.05), OV (p < 0.001), PRAD (p < 0.001), READ (p < 0.001), UCEC (p < 0.001) and UCS (p < 0.001). High expression of LAG3 correlates with longer overall survival (OS) in BLCA (HR = 0.67, p < 0.05), CESC (HR = 0.3, p < 0.001), HNSC (HR = 0.67, p < 0.01), LUSC (HR = 0.71, p < 0.05), OV (HR = 0.65, p < 0.01), STAD (HR = 0.68, p < 0.05), and UCEC (HR = 0.57, p < 0.01). Conversely, in KIRC (HR = 1.85, p < 0.001), KIRP (HR = 2.81, p < 0.001), and THYM (HR = 8.92, p < 0.001), high LAG3 expression corresponds to shorter OS. Comprehensive results for recurrence-free survival (RFS) indicate that LAG3 acts as a protective factor in BLCA, CESC, OV, and UCEC. Moreover, LAG3 is widely expressed in tumor-associated lymphocytes, positively correlating with tumor immune scores and stromal scores, and significantly present in the C2 immune subtype across various tumors. High LAG3 expression correlates with increased immune infiltration. LAG3 shows associations with MSI, TMB, and the MMR system, participating in multiple signaling pathways including the T cell receptor pathway. It also demonstrates positive correlations with sensitivity to eleven different drugs. Unlike traditional inhibitory immune checkpoints, LAG3 exhibits dual roles in clinical and immune prognostication across pan-cancers, making it a significant predictive factor. In some cancers, LAG3 serves as a risk factor, indicating adverse clinical outcomes. Conversely, in BLCA, CESC, OV, and UCEC, LAG3 acts as a protective factor associated with longer patient survival. LAG3 demonstrates strong associations within tumor immunity, participating in a range of immune and inflammatory signaling pathways. Elevated levels of LAG3 are linked not only to T cell exhaustion but also to increased immune infiltration and polarization towards M1 macrophages.
... Relapse or resistance to CAR T cell therapy is primarily due to either lack of T cell persistence or antigen loss [10]. A variety of cellular and molecular pathways can contribute to tumor low antigen density and/or antigen loss including localized loss-of-function mutations, alternative splicing, dysregulated trafficking to the cell surface, lineage switching, and trogocytosis [11,12]. ...
... Conversely, in the cancer setting, trogocytosis can play a significant role in tumor immune evasion and immune suppression. Cancer cells may exploit trogocytosis to escape immune surveillance, leading to a detrimental effect on antitumor immune responses [12,25]. For example, studies have shown that trogocytosis may hinder the effectiveness of CAR therapy by transferring CD19 from cancer cells to CAR T cells, resulting in the reduction of tumor antigen levels [25]. ...
... Additionally, CAR T cells that have acquired CD19 through trogocytosis can be recognized and destroyed by neighboring CAR T cells, a phenomenon known as fratricide [25]. Therefore, inhibiting trogocytosis may augment the effectiveness of CAR T cell therapy [12]. ...
Chimeric antigen receptor (CAR) NK and T cell therapy are promising immunotherapeutic approaches for the treatment of cancer. However, the efficacy of CAR NK/T cell therapy is often hindered by various factors, including the phenomenon of trogocytosis, which involves the bidirectional exchange of membrane fragments between cells. In this review, we explore the role of trogocytosis in CAR NK/T cell therapy and highlight potential strategies for its modulation to improve therapeutic efficacy. We provide an in-depth analysis of trogocytosis as it relates to the fate and function of NK and T cells, focusing on its effects on cell activation, cytotoxicity, and antigen presentation. We discuss how trogocytosis can mediate transient antigen loss on cancer cells, thereby negatively affecting the effector function of CAR NK/T cells. Additionally, we address the phenomenon of fratricide and trogocytosis-associated exhaustion, which can limit the persistence and effectiveness of CAR-expressing cells. Furthermore, we explore how trogocytosis can impact CAR NK/T cell functionality, including the acquisition of target molecules and the modulation of signaling pathways. To overcome the negative effects of trogocytosis on cellular immunotherapy, we propose innovative approaches to modulate trogocytosis and augment CAR NK/T cell therapy. These strategies encompass targeting trogocytosis-related molecules, engineering CAR NK/T cells to resist trogocytosis-induced exhaustion and leveraging trogocytosis to enhance the function of CAR-expressing cells. By overcoming the limitations imposed by trogocytosis, it may be possible to unleash the full potential of CAR NK/T therapy against cancer. The knowledge and strategies presented in this review will guide future research and development, leading to improved therapeutic outcomes in the field of immunotherapy.
... Notably, the trogocytic capacity and output are cell dependent. This process shapes the immune response by acting on both the trogocytotic and the antigen-presenting cells (For a recent review [19]). ...
Trogocytosis is an active process whereby fragments of plasma membrane proteins and cytoplasm are transferred from one cell to another in a cell-cell contact-dependent manner. T cells trogocytose pieces of the cells presenting antigen to them at the site of the immunological synapse. Fragments of the antigen-presenting cell membrane rich in antigen/major histocompatibility (MHC) complexes are internalized by the T cell. Those complexes are redirected to the plasma membrane of the T cell, which becomes an antigen-presenting cell to other T cells. Removing antigen/MHC complexes from professional and tumoral cells has consequences for the intensity and duration of the immune response. However, the acquired capacity of T cells to present the acquired cognate antigen/MHC complexes also affects the properties of the antigen-presenting trogocytotic T cells. Acting as antigen-presenting cells, trogocytotic CD4 T cells influence the differentiation of cytotoxic T cells and the differentiation of other CD4 T cells into pro-inflammatory effector T cells. Furthermore, trogocytosis of antigen/MHC complexes promotes the differentiation of the trogocytotic CD4 T cells towards regulatory T cells and Th2 effector cells. Trogoctyosis is, therefore, a parallel mechanism to signal transduction by membrane receptors, including the T cell antigen receptor, at the plane of the plasma membrane.
... One possible mechanism underlying the acquisition of HLA-DR expression is trogocytosis, the transfer of plasma membrane proteins from one cell to another following cell-cell contact. This process has been shown to be an important immunoregulatory mechanism impacting CD8+ T cell activation (32), and further studies are needed to determine its potential role in fHLH. ...
Familial hemophagocytic lymphohistiocytosis (fHLH) encompasses a group of rare inherited immune dysregulation disorders characterized by loss-of-function mutations in one of several genes involved in the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. The resulting defect in cytotoxicity allows these cells to be appropriately stimulated in response to an antigenic trigger, and also impairs their ability to effectively mediate and terminate the immune response. Consequently, there is sustained lymphocyte activation, resulting in the secretion of excessive amounts of pro-inflammatory cytokines that further activate other cells of the innate and adaptive immune systems. Together, these activated cells and pro-inflammatory cytokines mediate tissue damage that leads to multi-organ failure in the absence of treatment aimed at controlling hyperinflammation. In this article, we review these mechanisms of hyperinflammation in fHLH at the cellular level, focusing primarily on studies performed in murine models of fHLH that have provided insight into how defects in the lymphocyte cytotoxicity pathway mediate rampant and sustained immune dysregulation.
... As a result, T cells are subjected to the Ag-specific cytolysis by neighboring T cells (termed "fratricide"), which may lead to suppressed T cell immunity [163]. Meanwhile, T cells may also acquire p-MHCs from other target cells through contact-dependent immunological synapses, and Tregs are especially adept at removing MHC class II and costimulatory molecules from APCs via trogocytosis to induce immune tolerance [164]. In addition to T cell-based Ag receptors, NK cells [165,166] and basophils [167] can also acquire Ag from APCs, thereby impacting the potency, durability, and even consequence of immune responses. ...
Antigen transfer refers to the process of intercellular information exchange, where antigenic components including nucleic acids, antigen proteins/peptides and peptide-major histocompatibility complexes (p-MHCs) are transmitted from donor cells to recipient cells at the thymus, secondary lymphoid organs (SLOs), intestine, allergic sites, allografts, pathological lesions and vaccine injection sites via trogocytosis, gap junctions, tunnel nanotubes (TNTs), or extracellular vesicles (EVs). In the context of vaccine inoculation, antigen transfer is manipulated by the vaccine type and administration route, which consequently influences, even alters the immunological outcome, i.e., immune amplification and tolerance. Mainly focused on dendritic cells (DCs)-based antigen receptors, this review systematically introduces the biological process, molecular basis and clinical manifestation of antigen transfer.
... In groups 4, 6, 8, 10, 12 at which rats were administered the mushroom extracts in low doses of 200 mg/kg, spleens showed moderate white pulp depletion with increase the number of reticuloendothelial cells in red pulp and thymus showed mild reduced in lymphocytes population with mild lymphocytes apoptosis and macrophages phagocytized apoptotic debris as seen in Figs. 1 and 2D, F, H, J and I of Pleurotus ostreatus, Pleurotus columbinus, Pleurotus sajor-caju, Lentinula edodes and Agaricus bisporus respectively. On the other hand, groups 5,7,9,11,13 where mushroom was fed to rats in high doses of 400 mg/kg, spleen showed apparent normal white pulp with absence of germinal centers, increase number of lymphoblast, and lymphocytes were arranged in clusters. Some lymphocytes undergo apoptosis with proliferation of reticuloendothelial cells especially macrophages in red pulp and thymus showed moderate increase in lymphocytes population in both cortex and medulla with macrophages phagocytized apoptotic debris shown in Figs. 1 and 2E, G, I, K and M of P. ostreatus, P. columbinus, P. sajor-caju, L. edodes and A. bisporus, respectively. ...
Mushrooms are nutritious foods that are widely cultivated all over the world. They are rich in a range of compounds linked to improving functions of the immune system including carotenoids, alkaloids, lectins, enzymes, folates, fats, organic acids, minerals, polysaccharides, phenolics, proteins, tocopherols, terpenoids, and volatile compounds. In this study we investigated, the immunomodulatory activity in rats of the aqueous extracts of five of the most common edible mushrooms belonging to Family Basidiomycota-white-rot fungi including, Lentinula edodes, Agaricus bisporus , Pleurotus ostreatus , Pleurotus columbinus, and Pleurotus sajor-caju . Male Wistar albino rats were assigned to thirteen groups and Immunosuppression was induced by oral administration of dexamethasone (0.1 mg/kg), followed by oral administration of the mushroom extracts at low (200 mg/kg) and high (400 mg/kg) doses. A positive control group received the immune stimulant Echinacea extract Immulant® at (30 mg/kg), while the negative control group received only saline. From each animal, in each group, blood samples were collected after 15 days for complete blood counts and for measurement of immunologic parameters, including lysozyme activity, nitric oxide (NO) production and serum cytokines including tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin 1 beta (IL-1β) levels. Results have shown that white blood cells (WBCs) and lymphocytic counts were significantly boosted by high doses of each of the five mushroom extracts (207–289% increase for WBC and 153–175% for lymphocytes) with a significant increase in lysozyme activity (110–136% increase), NO concentration (159–232% increase) and cytokines as compared to the negative control group. Histopathological examination of the rats' spleen and thymus tissues has shown marked lymphocytic proliferation that was more obvious at the higher doses. In conclusion, our results showed that the five edible mushroom extracts revealed significant immunostimulatory effects preclinically particularly, at the higher doses (400 mg/kg) which can be considered the effective dose.
... Their communication has been cited in more than 300 publications, clearly demonstrating the immunological importance of trogocytosis. In the past 5 years, the general subject of trogocytosis has been reviewed extensively [2][3][4][5][6][7][8][9][10] and recent evidence indicates that trogocytosis impacts a number of immunologic phenomena including the action of CAR-T cells and checkpoint inhibitors [11][12][13][14]. We will focus this review on one subclass of trogocytosis that is mediated by the recognition of IgG immune complexes on donor cells by FcγR on acceptor cells. ...
There is increasing interest in the clinical implications and immunology of trogocytosis, a process in which the receptors on acceptor cells remove and internalize cognate ligands from donor cells. We have reported that this phenomenon occurs in cancer immunotherapy, in which cells that express FcγR remove and internalize CD20 and bound mAbs from malignant B cells. This process can be generalized to include other reactions including the immune adherence phenomenon and antibody-induced immunosuppression. We discuss in detail FcγR-mediated trogocytosis and the evidence supporting a proposed predominant role for liver sinusoidal endothelial cells via the action of the inhibitory receptor FcγRIIb2. We describe experiments to test the validity of this hypothesis. The elucidation of the details of FcγR-mediated trogocytosis has the potential to allow for the development of novel therapies that can potentially block or enhance this reaction, depending upon whether the process leads to unfavorable or positive biological effects.
... On the other hand, the PI state may have implications during T cell activation. TCR-CD3 complexes that are already attached to peptides previously transferred from MHCs, similar to the event of 'trogocytosis'[267][268][269][270], may reduce the overall magnitude of antigen recognition in a following signalling event when clustered at the T cell-APC interface. Experimental approaches such as mass spectrometry may be employed to detect peptide bound to TCRs on T cell ...
The T cell antigen receptor (TCR-CD3) is an octameric protein complex located in the T cell plasma membrane. It plays a vital role in our adaptive immune system by recognising a wide variety of antigenic peptides attached to major histocompatibility complexes (pMHCs). Upon binding with pMHCs, the TCR-CD3 transmits a signal to its unstructured cytoplasmic region which undergoes phosphorylation by the lymphocyte-specific protein tyrosine kinase (LCK), further triggering a chain of events ultimately aiding in T cell-mediated immune response. Despite studies conducted on the structure and function of the TCR-CD3 and LCK, we do not yet understand the initial phase of T cell activation in molecular detail. To achieve this, it is important to not only know their structure but also study their dynamic behaviour in their native environment on the nanosecond to microsecond time-scales. Given the lack of structural data on the TCR-CD3 cytoplasmic region and the full-length LCK, molecular modelling employed in this thesis has helped produce their complete models and enabled molecular dynamics simulation studies. Supported by prior experimental evidence, the simulations conducted in this thesis have led to novel findings such as: (i) specific sites in the TCR-CD3 transmembrane region that potentially help transmit pMHC-induced signals into the cytoplasmic region, (ii) TCR-CD3 dynamics in a membrane and the arrangement of its cytoplasmic region, (iii) PIP lipid interactions and clustering around the TCR-CD3 and upon the association of LCK with the membrane, (iv) TCR-CD3 conformational changes, and (v) protein-protein/lipid interactions in the open and closed LCK conformations. Overall, this thesis provides novel molecular-level insights into the dynamics of the TCR-CD3 and LCK, and also signifies the potential of molecular dynamics simulations in studying membrane-associated proteins. Further, this work encourages computational studies of other immunoreceptors to help understand various immune mechanisms and aid in clinical therapeutics.
... In a biological sense, trogocytosis participates in the elimination of invading pathogens and tumor cells to protect the body. On the other hand, in an immunological sense, trogocytosis is implicated in the activation or inhibition for the immune homeostasis [137][138][139]. ...
Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cells in the circulation. These cells act as the fast and powerful defenders against environmental pathogenic microbes to protect the body. In addition, these innate inflammatory cells can produce a number of cytokines/chemokines/growth factors for actively participating in the immune network and immune homeostasis. Many novel biological functions including mitogen-induced cell-mediated cytotoxicity (MICC) and antibody-dependent cell-mediated cytotoxicity (ADCC), exocytosis of microvesicles (ectosomes and exosomes), trogocytosis (plasma membrane exchange) and release of neutrophil extracellular traps (NETs) have been successively discovered. Furthermore, recent investigations unveiled that PMNs act as a double-edged sword to exhibit paradoxical activities on pro-inflammation/anti-inflammation, antibacteria/autoimmunity, pro-cancer/anticancer, antiviral infection/COVID-19-induced immunothrombotic dysregulation. The NETs released from PMNs are believed to play a pivotal role in these paradoxical activities, especially in the cytokine storm and immunothrombotic dysregulation in the recent SARS-CoV-2 pandemic. In this review, we would like to discuss in detail the molecular basis for these strange activities of PMNs.
