Trogocytosis

Trogocytosis (from the Ancient Greek trōgō, "to gnaw" or "to nibble," and kytos, "cell") is an active, contact-dependent cellular process in which one living cell extracts intact patches of plasma membrane—complete with embedded transmembrane receptors, lipid rafts, and underlying cortical cytoplasm—directly from a conjugated living donor cell within minutes of cell–cell contact (Joly & Hudrisier, 2003; Dance, 2019). First characterized at the immunological synapse of T lymphocytes, B lymphocytes, and natural killer (NK) cells by Etienne Joly and Denis Hudrisier in 2003, trogocytosis is mechanistically distinct from both phagocytosis (which engulfs an entire dead or opsonized target cell or microbe into a phagolysosome) and exosome / extracellular vesicle transfer (which operates across fluid spaces without requiring direct receptor-mediated cell conjugation). Across immunology, neurobiology, and parasitology, trogocytosis mediates antigen cross-dressing, CTLA-4 immune checkpoint trans-endocytosis, chimeric antigen receptor (CAR)-T cell target antigen escape, microglial synaptic pruning, and the cytolytic killing of human intestinal cells by Entamoeba histolytica (Ralston et al., 2014; Hamieh et al., 2019).

When a T lymphocyte (TCR), B lymphocyte (BCR), or NK cell (NKG2D / KIR) forms an immunological synapse with an antigen-presenting cell (APC) or tumor cell, high-avidity receptor clustering in the central supramolecular activation cluster (cSMAC) initiates a three-step mechanical and endocytic pinch-off:

1. Receptor Clustering and Cortical F-Actin Remodeling: Engagement of the TCR by cognate peptide–MHC (pMHC) complexes—or of the inhibitory checkpoint receptor CTLA-4 by costimulatory ligands CD80 (B7-1) and CD86 (B7-2)—activates Src-family kinases (Lck/Fyn), Syk/ZAP-70, PI3K, and the small Rho-family GTPases Tc21 (R-Ras2) and RhoG (Martínez-Martín et al., 2011). Blocking cortical actin polymerization with cytochalasin D or latrunculin A completely abolishes trogocytosis in T and NK cells (whereas B-cell BCR trogocytosis can proceed via high-affinity mechanical pulling alone).
2. Clathrin/Dynamin Pinch-Off and Membrane Scission: As the lymphocyte either internalizes its own TCR/BCR microclusters into multivesicular endosomes or physically pulls backward to break the conjugate, the high mechanical bond strength of the TCR–pMHC or CAR–antigen complex exceeds the lateral cohesive strength of the donor cell's lipid bilayer. Assisted by dynamin GTPase scission, the acceptor cell rips a 50- to 500-nanometer membrane patch out of the donor cell's surface while the donor cell rapidly reseals the micro-lesion using Ca²⁺-dependent lysosome exocytosis and ESCRT-III machinery.
3. Recycling to the Acceptor Cell Surface ("Cross-Dressing"): Once internalized inside Tc21/RhoG-positive endosomes in the acceptor T or NK cell, the stolen donor membrane patch fuses back with the acceptor cell's own plasma membrane—displaying the donor's intact MHC class I, MHC class II, CD80, CD86, or PD-L1 molecules right side out on the lymphocyte surface!

1. CTLA-4 Trans-Endocytosis (Trogocytic Stripping of CD80/CD86)

How does the checkpoint receptor CTLA-4 expressed on regulatory T cells (T_regs) suppress autoimmune activation of naive T cells? In 2011, Omar S. Qureshi, Lucy S. K. Walker, and David M. Sansom discovered that CTLA-4 acts via trogocytic trans-endocytosis:

• T_regs bind CD80 and CD86 on the surface of dendritic cells with 10- to 20-fold higher affinity than the activating receptor CD28, physically rip CD80 and CD86 molecules out of the dendritic cell membrane via trogocytosis, and degrade them inside the T_reg's lysosomes.
• Stripped of its CD80/CD86 costimulatory ligands, the dendritic cell can no longer provide Signal 2 to naive conventional T cells, enforcing peripheral immune tolerance (Qureshi et al., 2011).

2. Dendritic Cell "Cross-Dressing" for Viral CD8⁺ T-Cell Priming

During viral infections or allogeneic organ transplantation, uninfected lymphoid-resident dendritic cells use trogocytosis to acquire pre-formed peptide–MHC class I complexes directly from the surface of neighboring virus-infected or donor cells ("cross-dressing"), allowing them to prime naive CD8⁺ cytotoxic T lymphocytes immediately without requiring intracellular proteasome processing or TAP transport (Wakim & Bevan, 2011).

3. Neutrophil and Macrophage Antibody-Dependent Trogocytosis ("Trogoptosis")

When tumor cells are coated with therapeutic monoclonal antibodies (such as anti-HER2 trastuzumab or anti-CD20 rituximab), neutrophils and macrophages engage the antibody Fc region via FcγRIIA / FcγRIIIA and execute repeated antibody-dependent cellular trogocytosis—ripping dozens of consecutive membrane bites out of the cancer cell until its plasma membrane ruptures osmotically, a non-apoptotic lytic death mode termed trogoptosis (Matlung et al., 2018). Conversely, with anti-CD20 rituximab in chronic lymphocytic leukemia (CLL), hepatic Kupffer cells and monocytes sometimes shave CD20–rituximab complexes off the surface of leukemic B cells without killing them ("antigenic modulation / shaving"), leaving the surviving CD20-negative leukemia cells invisible to further antibody therapy (Beum et al., 2006).

In 2019, Mohamad Hamieh, Michel Sadelain, and colleagues at Memorial Sloan Kettering Cancer Center discovered that trogocytosis is a primary mechanism of reversible antigen-low relapse and T-cell exhaustion in Chimeric Antigen Receptor (CAR)-T cell therapy (such as CD19-CAR or BCMA-CAR):

• Because synthetic CAR constructs use single-chain variable fragments (scFvs, such as FMC63 in anti-CD19 CARs) that bind target tumor antigens with nanomolar antibody affinity (100- to 1,000-fold tighter than natural micromolar TCR–pMHC bonds), when a CAR-T cell contacts a B-cell leukemia cell, it strips CD19 molecules off the leukemia cell surface via trogocytosis and transfers them onto the CAR-T cell's own membrane within minutes!
• This causes a dual therapeutic failure:
  1. Target Antigen Escape on the Tumor Cell: The leukemia cell's surface CD19 density drops below the threshold (~200–1,000 molecules/cell) required to trigger CAR-T cytolysis, allowing the "CD19-dim" tumor cell to escape killing without mutating the CD19 gene.
  2. CAR-T Fratricide and Exhaustion: The CAR-T cell, now decorated ("cross-dressed") with stolen CD19 protein on its own surface, is recognized as a tumor target and killed by neighboring CAR-T cells ("fratricide"), while chronic self-signaling drives PD-1/LAG-3/TIM-3 T-cell exhaustion (Hamieh et al., 2019). Designing lower-affinity, fast-off-rate CARs or inhibiting cholesterol-dependent membrane transfer with PCSK9 / cholesterol metabolic modulators prevents CAR trogocytosis and restores durable tumor clearance.

For more than a century, the protozoan parasite Entamoeba histolytica—the causative agent of human amoebic dysentery and liver abscess (named histolytica for "tissue-dissolving")—was assumed to kill human intestinal epithelial cells and lymphocytes by secreting soluble toxins first and then phagocytosing the dead corpse. In 2014, Katherine S. Ralston, William A. Petri Jr., and colleagues overturned this paradigm using live high-speed two-photon microscopy:

• When an E. histolytica trophozoite adheres to a living human Jurkat T cell or intestinal enterocyte via its Gal/GalNAc lectin, the amoeba refuses to engulf the living cell whole. Instead, driven by amoebic PI3K, EhC2PK, and actin polymerization, the amoeba stretches a tubular invagination into the host cell and bites off and ingests discrete membrane-and-cytoplasm fragments ("amoebic trogocytosis") within 1 minute of contact!
• After the amoeba takes 5 to 15 successive bites, the human cell suffers a catastrophic intracellular Ca²⁺ surge, loses plasma membrane integrity, and dies. Crucially, the moment the human cell dies, the amoeba stops nibbling, detaches, and walks away from the dead corpse—only performing classical whole-cell phagocytosis on cells that were already dead prior to contact. Furthermore, by displaying human membrane proteins (MHC class I and CD59/CD46 complement regulatory proteins) stolen during amoebic trogocytosis on its own surface, E. histolytica camouflages itself against lysis by human serum complement inside the bloodstream (Miller et al., 2019).

1. Joly, E., & Hudrisier, D. (2003). "What is trogocytosis and what is its purpose?" Nature Immunology, 4(9), 815. https://doi.org/10.1038/ni0903-815
2. Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., et al. (2011). "Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4." Science, 332(6029), 600–603. https://doi.org/10.1126/science.1202947
3. Ralston, K. S., Solga, M. D., Mackey-Lawrence, N. M., Somlata, Bhattacharya, A., & Petri, W. A. Jr. (2014). "Trogocytosis by Entamoeba histolytica contributes to cell killing and tissue invasion." Nature, 508(7497), 526–530. https://doi.org/10.1038/nature13242
4. Matlung, H. L., Babes, L., Zhao, X. W., van Houdt, M., Treffers, L. W., van Rees, D. J., et al. (2018). "Neutrophils kill antibody-opsonized cancer cells by trogoptosis." Cell Reports, 23(13), 3946–3959.e6. https://doi.org/10.1016/j.celrep.2018.05.082
5. Hamieh, M., Dobrin, A., Cabriolu, A., van der Stegen, S. J. C., Giavridis, T., Mansilla-Soto, J., et al. (2019). "CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape." Nature, 568(7750), 112–116. https://doi.org/10.1038/s41586-019-1054-1