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Shaping of T Cell Functions by Trogocytosis cells Review Shaping of T Cell Functions by Trogocytosis Masafumi Nakayama *, Arisa Hori, Saori Toyoura and Shin-Ichiro Yamaguchi Laboratory of Immunology and Microbiology, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga 525-8577, Japan; [email protected] (A.H.); [email protected] (S.T.); [email protected] (S.-I.Y.) * Correspondence: [email protected]; Tel.: +81-77-599-3264 Abstract: 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 observed. For instance, antigen-presenting cells (APCs) acquire MHC class I (MHCI) from allografts, tumors, and virally infected cells, and these APCs are subsequently able to prime CD8+ T cells without antigen processing via the preformed antigen-MHCI complexes, in a process called cross-dressing. T cells also acquire MHC molecules from APCs or other target cells via the immunological synapse formed at the cell-cell contact area, and this phenomenon impacts T cell activation. Compared with naïve and effector T cells, T regulatory cells have increased trogocytosis activity in order to remove MHC class II and costimulatory molecules from APCs, resulting in the induction of tolerance. Accumulating evidence suggests that trogocytosis shapes T cell functions in cancer, transplantation, and during microbial infections. In this review, we focus on T cell trogocytosis and the related inflammatory diseases. Keywords: acquisition; nibbling; stripping; cross-dressed; cross-presentation; dendritic cell (DC); TCR; Treg; chimeric antigen receptor (CAR); fratricide; escape variant Citation: Nakayama, M.; Hori, A.; Toyoura, S.; Yamaguchi, S.-I. Shaping of T Cell Functions by Trogocytosis. Cells 2021, 10, 1155. https://doi.org/ 10.3390/cells10051155 1. Introduction In order to communicate with each other, immune cells express a wide variety of cell Academic Editors: Ryuta Koyama surface molecules such as receptors, ligands, and adhesion molecules. Cell-cell communica- and Kumiko Nakada-Tsukui tion is required for the generation of appropriate immune responses to various pathogens. It has been established that during cell-cell interactions, membrane-associated proteins Received: 3 April 2021 are transferred between immune cells [1–4]. In the past this biological phenomenon has Accepted: 6 May 2021 been called acquisition, nibbling, or stripping, and is currently referred to as trogocytosis, Published: 10 May 2021 derived from the ancient Greek word Trogo, meaning ‘gnaw’ [5]. In contrast to phagocytosis (Phago is the Greek meaning ‘to eat’), which is executed by phagocytes such as macrophages Publisher’s Note: MDPI stays neutral and dendritic cells (DCs), trogocytosis is considered to be executed by any type of cells, as with regard to jurisdictional claims in described below. By acquiring membrane-associated proteins, so-called recipient cells gain published maps and institutional affil- alternative cellular functions. In contrast, donor cells may lose these proteins and cellular iations. functions (Figure1). In addition, under certain conditions, bi-directional trogocytosis is observed [6] (see Section2). In some cases, trogocytosis mediates the intercellular transfer not only of plasma membranes but also of intracellular contents [7,8], which may also alter cellular functions. However, this possibility has not been extensively investigated. Copyright: © 2021 by the authors. The best characterized trogocytosis involves the transfer of major histocompatibil- Licensee MDPI, Basel, Switzerland. ity complex (MHC) molecules from antigen-presenting cells (APCs) to T cells during This article is an open access article their interactions [1,3]. Trogocytosis of MHC molecules shapes T cell functions and is distributed under the terms and involved in various T cell-mediated diseases. Trogocytosis has been observed not only in conditions of the Creative Commons immune cell interactions, but also during epithelial cell communication [9] and in neu- Attribution (CC BY) license (https:// ronal synapses [10,11]. Further, trogocytosis is used by amoebae to kill host cells [12,13], creativecommons.org/licenses/by/ indicating that this biological phenomenon is widely conserved throughout eukaryotes. 4.0/). Cells 2021, 10, 1155. https://doi.org/10.3390/cells10051155 https://www.mdpi.com/journal/cells Cells 2021, 10, 1155 2 of 16 Cells 2021, 10, 1155 2 of 16 that this biological phenomenon is widely conserved throughout eukaryotes. Recent find- ings of trogocytosis in microbes [14], mammalian neuronal networks [15,16], and non-T Recent findings of trogocytosis in microbes [14], mammalian neuronal networks [15,16], cell immune cell interactions [2,17,18] have been well summarized by others previously and non-T cell immune cell interactions [2,17,18] have been well summarized by others and also in this issue. Thus, here we mainly focus on T cell trogocytosis and related dis- previously and also in this issue. Thus, here we mainly focus on T cell trogocytosis and eases. related diseases. Figure 1. Principal models of trogocytosis. When two types of cells make physical contact via receptor-ligand interactions, Figure 1. Principal models of trogocytosis. When two types of cells make physical contact via receptor-ligand interactions, the driving force for internalization of receptors expressed on one cell (here called recipient) co-opts ligand-containing the driving force for internalization of receptors expressed on one cell (here called recipient) co-opts ligand-containing plasmaplasma membrane membrane fra fragmentsgments from from the the other other cell cell (here (here called called donor donor).). Not Not only only are are receptors receptors and and ligands ligands involved involved in in this this process,process, but but adhesion adhesion molecules molecules also also play play a arole. role. The The donor donor cells cells lose lose membrane membrane molecules molecules and and their their cellular cellular functions, functions, whereaswhereas the the recipient recipient cells cells gain gain don donor-derivedor-derived membrane membrane molecules molecules and and functions. functions. It is unclear It is unclear how donor how donor-derived-derived mol- eculesmolecules exist existon recipient on recipient cells. cells. The three The three hypothesized hypothesized models models are shown are shown as A, as B, A, and B, C. and C. 2.2. Possible Possible Mechanisms Mechanisms Underlying Underlying Trogocytosis Trogocytosis TheThe molecular molecular mechanisms mechanisms underlying underlying trog trogocytosisocytosis are are not not fully fully understood. understood. How- How- ever,ever, trogocytosis trogocytosis of of the the T T cell cell receptor receptor ( (TCR)TCR) and and MHC MHC receptor receptor ligand ligand pair pair has has been been extensivelyextensively characterized. characterized. Of Of note, note, Martinez Martinez-Martin-Martin et et al. al. have have shown shown that that T T cells cells acquire acquire MHCMHC class class I I(MHCI (MHCI)) from from APCs APCs through through the the action action of of small small GTPases GTPases such such as as RhoG RhoG and and TC21TC21 [19] [19.]. RhoG RhoG is isknown known to tobe be involved involved in inphagocytosis phagocytosis [20] [20, and], and thus thus trogocytosis trogocytosis is characterizedis characterized as incomplete as incomplete phagocytosis. phagocytosis. Indeed, Indeed, PI3K PI3Kinhibitors inhibitors effectively effectively inhibit inhibit TCR trogocytosisTCR trogocytosis [19,21] [.19 Likewise,,21]. Likewise, natural naturalkiller (NK killer) cells (NK) expressing cells expressing NKG2D, NKG2D, an NK activat- an NK ingactivating receptor, receptor, acquire acquire ligands, ligands, including including RaeI, RaeI,MICA MICA,, and andMICB, MICB, from from tumor tumor cells cells via via a PI3Ka PI3K-dependent-dependent pathway pathway [22] [22. Taken]. Taken together, together, trogocytosis trogocytosis appears appears to to be be accompanied accompanied byby recipient recipient cell cell receptor receptor internal internalizationization ( (FigureFigure 1)).. DonorDonor cells cells may may actively actively release release their their membrane membrane fragments fragments to to recipient recipient cells. cells. These These membranemembrane fragments fragments may may include include extracellular extracellular vesicles vesicles ( (EVs)EVs) [23] [23].. Choudhuri Choudhuri et et al. al. have have shownshown that that TCR TCR signaling signaling leads leads to to secretion secretion of of TCR TCR-enriched-enriched micr microvesiclesovesicles via via the the central central supramolecularsupramolecular activation activation cluster cluster (c (c-SMAC)-SMAC) [24] [24.]. Sorting Sorting of of TCR TCR to to the the c c-SMAC-SMAC and and the the productionproduction of of EVs EVs isis dependent dependent on on tumor tumor susceptibility susceptibility gene gene 101 101 (TSG101 (TSG101),), an essential an essen- tial component of the endosomal sorting complex required for transport (ESCRT)-I [25]. These EVs are transferred to and activate neighboring B cells [24]. On the other hand, Cells 2021, 10, 1155 3 of 16 Kim et al. have reported that TCR signaling causes TCR-enriched microvilli particles, called T cell
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