TROGOCYTOSIS
Trogocytosis, a form of cell-to-cell interaction widely existing in a species or between different species, involves one cell contacting and quickly “biting” another cell. This interaction was first described in 1970 as part of the process of parasites attacking and killing host cells (1).
In 2002,it was given its name from the ancient Greek word “trogo”, which means “nibbling” to describe the phenomenon of the transfer of membrane fragments containing membrane-anchored proteins between cells (2).
Recently, an increasing number of studies have shown that trogocytosis plays a vital role in the immune system, including antigen presentation, T cell differentiation, immune regulation, and antiinfection and anti-tumor immunity (3–19).
Many types of proteins are transferred between cells by trogocytosis, including MHC (major histocompatibility complex) molecules, costimulatory molecules, adhesion molecule receptors, tumor antigens, and the antigens of pathogens (9, 18, 20–27).
The involved cell types include T cells (gd T cells, and CD4+ and CD8+ ab T cells), B cells, NK cells, dendritic cells, monocytes/macrophages, neutrophils, endothelial cells, fibroblasts, eosinophils, basophils), tumor cells, and pathogen cells (e.g., viruses, bacteria, and parasites) (9, 18, 20–28).
Trogocytosis is strictly contactdependent between living cells. Previous studies have shown that MHC I or HLA-C molecules on the surface of target cells of mice or humans are bidirectionally exchanged with the inhibitory receptor KIR (NK cell Ig-like receptor) of NK cells within a few minutes after coculture by immunological synapses (29, 30). In addition, Ralston et al. showed that amoebae only gnawed live-cell targets and directly engulfed dead cell corpses, which is one of the characteristics of trogocytosis (31).
Interestingly, the membrane molecules obtained by trogocytosis, such as human leukocyte antigen (HLA)-C, peptide-MHC complexes and inhibitory natural killer cell receptors, can be recolonized on the surface of trogocytosispositive cells without proteolytic cleavage and perform corresponding functions (29, 30, 32). The outcomes of trogocytosis, which vary with recipient cells, have changed our cognition of some classical theories. Trogocytosis does not always lead to the death of target cells. The interaction is relatively mild and tends to take up material and exchange information under physiological conditions, while it is often strong and usually ends in the death of target cells under pathological conditions (14, 20, 33). The existence of trogocytosis has shaken the traditional notion that cells can only perform their inherent functions or that a gene must be transcribed to use its protein product.
With trogocytosis, even mature cells can perform a variety of unconventional functions, and these functions strictly depend on the cellular environment; that is, trogocytosis leads to very different functional consequences with similar processes in different states (34). However, is its function ultimately good or bad? From different perspectives, the role of trogocytosis also shifts between friend and foe in different environments. The reported physiological processes and related diseases involved in trogocytosis are summarized, divide into two aspects (i.e., friend and foe) and shown in Figure 1. Specifically, “Friend” refers to the biological events that trogocytosis is beneficial to appropriately enhancing human immunity and improving the ability to resist diseases, whereas “Foe” means the biological events that trogocytosis promotes the occurrence and development of diseases and harms human health.
TROGOCYTOSIS IN THE IMMUNE SYSTEM
The Immune System Transmits Signals Among Cells by Trogocytosis
The communication of immune cells involves various mechanisms, including immune synapses, nanotubes, trogocytosis, and exosomes. The transfer of membrane proteins of cells mediated by trogocytosis, including MHC molecules, CD3, costimulatory molecules, endothelial cell molecules, NK receptors, chemokine receptors, and glycosylphosphatidylinositol (GPI)-anchored proteins, widely occurs in T cells, B cells, macrophages, DC, NK cells. The interaction has modified the functions of immune cells involving in antigen presentation, information transfer, and regulation and homeostasis (3, 22, 25, 35–42).
In general, the typical manner for antigen presentation is that professional APCs (such as DCs) process the protein antigens into pMHCs (antigenic peptide-MHC complexes) and then present them to T cells. Some researches revealed a new antigen presentation pathway in which APCs and non-APCs directly obtained preformed pMHCs on the surface of target cells by trogocytosis and activated T cells without further processing (7, 10, 14, 19). Subsequently, the trogocytosis of MHCs occurs not only in T cell-APCs but also in T cell-endothelial cells, APCAPCs, APC-NK cells, tumor cell-T cells, and NK cells (43–47). For example, the transfer of pMHCs and CD80 from APCs to T cells could regulate T cell proliferative signals and sustain their activation in the absence of APCs (32, 48–50).
At later time points, the number of activated CD4+ T cells trogocytosing and capturing MHC-peptide complexes increases and outnumbers the APCs, there is increasing probability that newly arriving T cells (and any T cells that have just been activated and need a second hit to continue to divide) would encounter them before encountering a proper professional APC. This T-T interaction leads to the inhibition of the newly arriving T cells and the Agexperienced T cells, whereas naive T cells encountering antigenpresenting T cells are not inactivated, rather they are activated (51).
In addition, Miyake et al. found that basophils gnawed DCs to obtain membrane fragments containing pMHC II and stimulated the proliferation of peptide-specific T cells, which indicated that trogocytosis could enhance the antigen presentation ability of basophils (52). CD4+ T cells can obtain not only MHCs or pMHCs from APCs by trogocytosis but also costimulatory molecules (CD28, CD54, CD80) from APCs to deliver costimulatory signals to activate CD4+ T cells (48, 53, 54). Zhou et al. showed that MHC II and CD80 in CD4+ T cells maintained the activation of T cells in the absence of APC, which was an important factor in maintaining the homeostasis of memory T cells (50).
Interestingly, the trogocytosed molecules might be unmodified in the recipient cell to perform their corresponding function. For example, Reed et al. reported that trogocytosis-mediated signaling has the potential to uniquely modulate the effectorcytokine production and differentiation of trog+ CD4+ T cell after separation from APC. To be more specific, trogocytosismediated intracellular signaling in CD4+ T cells drove Th2- associated effector cytokine production and differentiation (15). They found that trogocytosed molecules (pMHC complexes and costimulatory molecules) on trog+ CD4+ T cells engaged their cognate receptors and drove the expression of IL-4 and GATA-3 in sequence, which was consistent with the differentiation of helper T cells type 2 (Th2) (6, 15, 16).
Furthermore, extended trogocytosis-mediated signaling in CD4+ T cells resulted in the expression of Bcl-6, programmed cell death protein 1 (PD-1), CXCR5, and IL-21, which was consistent with the differentiation of follicular helper T cells (Tfhs) (5, 16). At the same time, IL-21 promoted the activation and survival of T cells and the generation of memory cells (55–59). On the other hand, trogocytosis might also affect the function of donor cell by removing some molecules from the donor cells. Qureshi et al. show that CTLA-4-expressing cells captured and removed CD80/CD86 from opposing cells to result in impaired costimulation via CD28, which revealed a mechanism of immune regulation whereby CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands (60).
In addition to the transmission of costimulatory signals, trogocytosis also mediates other signals to be transmitted between different immune cells, which maintains immune homeostasis by balancing the activation and suppression of immune responses. It was recently reported that antigenspecific Treg cells form strong interactions with DCs to acquire DC-derived membranes by a process of trogocytosis, resulting in selective depletion of the complex of cognate pMHC II from the DC surface, reducing the capacity of DCs to present antigens (3). The strong binding of Tregs and their capacity to debilitate DC function in an antigen-specific manner, represents a novel pathway involving trogocytosis for Treg–mediated suppression and may be a mechanism by which Treg cells maintain immune homeostasis (3, 61).
Trogocytosis also participates in the immunosuppressive effect mediated by Tregs in other ways. Tekguc et al. showed that Treg-expressed CTLA-4 depleted CD80/CD86 by trogocytosis and released free PD-L1 on APCs, which led to dual suppressive effects on T cell immune responses by limiting CD80/CD86 costimulatory naïve T cells and by increasing free PD-L1 available for the inhibition of effector T cells expressing PD-1 (17). Moreover, T cell microvilli-derived particles (TMPs) carrying T cell receptors (TCR) at all stages of T cell activation were separated from T cells by trogocytosis or membrane budding, which were deposited at the surface of cognate APCs to be a potentially effective pathway to transmit information on T cells to APCs (9). It is reported that human CD8+ T cells played a regulatory role in the immune response by obtaining inhibitory molecules from APCs (62). Studies have shown that human CD8+ T cells obtained functional programmed death-ligand 1 (PD-L1) from APCs in an antigen-specific manner, which led to the apoptosis of neighboring T cells with the expression of the receptor of PD-1 (62). Gary et al. reported that the inhibitory molecule PD-L1 and the receptor PD-1 expressed on various human cells were transferred between immune cells by trogocytosis to regulate the immune response and recycle the molecule (62). In addition to T cells, the antigen presentation and information transfer by trogocytosis also occurs in B cells. Soluble antigens can be bound to the B cell antigen receptor (BCR), and then internalized and presented to T cells by B cells, which initiates the humoral immune response. However, antigens are often insoluble or tethered to the cell surface. It has been reported that B cells can extract and present antigens that is tethered tightly to a noninternalizable surface and the evidence points to the major role being played by BCR-mediated wrenching of the antigen from its tether (63). Notably, a weak BCR can apparently wrench a tightly tethered antigen from the plate through continuous accumulation of effect in cases where the affinity difference is of several orders of magnitude (63). The nonstatic BCR antigen tether interaction and the motile nature of the cell may cause distortion of the antigen (and diminution of antigen tether affinity) (63). In addition, Xu et al. found that the BCR interacted with antigen-antibody complexes to remove epitopes from red blood cells by trogocytosis so that IgG could mediate the inhibitory effect on the immune response to antigens (27). Furthermore, the trogocytosis also affects the functions of macrophages, DC, and NK cells. The trogocytosis by T cells is usually a process of the acquisition of antigens and signal transmission. In addition to the above functions, the trogocytosis by monocytes also involves a process of removing antigens, which show that the acquirer cell may control the functional outcome of trogocytosis (38). It was reported that the trogocytosis by macrophages mediated by FcgR affects the function of target cells, such as T cells and NK cells, but does not obtain new proteins or new functions (41). It is reported that KIR+ NK cells generally did not express CCR7; however, they were able to extract CCR7 from CCR7+ cells by trogocytosis to migrate to the site of killing mature DCs and T lymphoblasts with the help of chemokines CCL19/CCL21 (39, 40, 42). Thus, the results showed that trogocytosis was widely involved in antigen presentation, information transfer, and regulation (activation, suppression, and even killing) of immune cells in the immune process, which was of greatly significance to the performance and homeostasis of immune function. Regrettably, the research on whether trogocytosed molecules undergoes degradation, modification and other processes before performing subsequent functions is so lacking that we know very little about this important issue. In addition, how cell membrane integrity is restored post trogocytosis is still a meaningful and not fully recognized process. In summary, our understanding of trogocytosis remains at a relatively superficial level and there are still many unknown fields waiting for us to explore, which also points out the direction for future research.