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The past decade witnessed a huge interest in the communication machinery called tunneling nanotubes (TNTs) which is a novel, contact-dependent type of intercellular protein transfer (IPT). As the IPT phenomenon plays a particular role in the cross-talk between cells, including cancer cells as well as in the immune and nervous systems, it therefore participates in remodeling of the cellular networks. The following review focuses on the placing the role of tunneling nanotube-mediated protein transfer between distant cells. Firstly, we describe different screening methods used to study IPT including tunneling nanotubes. Further, we present various examples of TNT-mediated protein transfer in the immune system, cancer microenvironment and in the nervous system, with particular attention to the methods used to verify the transfer of individual proteins.

Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.

The past decade witnessed a huge interest in the communication machinery called tunneling nanotubes (TNTs) which is a novel, contact-dependent type of intercellular protein transfer (IPT). As the IPT phenomenon plays a particular role in the cross-talk between cells, including cancer cells as well as in the immune and nervous systems, it therefore participates in remodeling of the cellular networks. The following review focuses on the placing the role of tunneling nanotube-mediated protein transfer between distant cells. Firstly, we describe different screening methods used to study IPT including tunneling nanotubes. Further, we present various examples of TNT-mediated protein transfer in the immune system, cancer microenvironment and in the nervous system, with particular attention to the methods used to verify the transfer of individual proteins., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Turos-Korgul, Kolba, Chroscicki, Zieminska and Piwocka.)

Trogocytosis is the uptake of membranes from one cell by another. Trogocytosis has been demonstrated for monocytes, B cells, T cells, and NK cells. The acquisition of the tolerogenic molecule HLA-G by T cells and NK cells makes them behave as regulatory cells. We investigated here whether HLA-G, which is expressed by tumor cells in vivo, could be acquired by monocytes and if this transfer could have functional consequences. We demonstrate that resting, and even more so, activated monocytes efficiently acquire membrane-bound HLA-G from HLA-G tumor cells by trogocytosis. However, we demonstrate that HLA-G quickly disappears from the surface of the monocytes in contrast to the HLA-G acquired by T cells. Consequently, HLA-Gacq+ monocytes do not reliably inhibit the on-going proliferation of autologous activated T cells and do not inhibit their cytokine production. Thus, we show that the acquirer cell may control the functional outcome of trogocytosis. [ABSTRACT FROM AUTHOR]

Abstract: The recent recognition of new types of cell–cell communication pathways challenges classic theories of cell autonomy. Evidence of functional “proteome mixing” among interacting cells, particularly immune cells, supports the notion that no cell is an island, and that even these “unsplittable” units are actually non-autonomous. We summarize various mechanisms of intercellular transfer of proteins—trans-endocytosis, trogocytosis, exosomal transport, shuttle through nanotubes, and cell-contact-dependent intercellular transfer of intracellular proteins including oncogenic Ras. These phenomena suggest exciting new possibilities for proteome research, focusing on system-level proteomics that characterize cell contents and functions in the context of intercellular protein transfer. [Copyright &y& Elsevier]

Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans -endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil (Sarcophilus harrisii) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumors. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily divergent species. • Key immune checkpoint receptor-ligand interactions are conserved in marsupials. • Live cell-based assays show Tasmanian devil CD28 and CTLA4 can capture CD80 and CD86 in trans from adjacent cells. • Mutation of the conserved CTLA4 MYPPPY ligand binding motif to CTLA4 MYPPPA reduces binding to CD80. • Removal of conserved CTLA4 YVKM protein recycling binding motif in CTLA4 alters intercellular protein transfer patterns. • Human immune checkpoint immunotherapies have the potential to be translated for veterinary and conservation medicine. [ABSTRACT FROM AUTHOR]

The homeodomain is found in hundreds of transcription factors that play roles in fate determination via cell-autonomous regulation of gene expression. However, some homeodomain-containing proteins (HPs) are thought to be secreted and penetrate neighboring cells to affect the recipient cell fate. To determine whether this is a general characteristic of HPs, we carried out a large-scale validation for intercellular transfer of HPs. Our screening reveals that intercellular transfer is a general feature of HPs, but it occurs in a cell-context-sensitive manner. We also found the secretion is not solely a function of the homeodomain, but it is supported by external motifs containing hydrophobic residues. Thus, mutations of hydrophobic residues of HPs abrogate secretion and consequently interfere with HP function in recipient cells. Collectively, our study proposes that HP transfer is an intercellular communication method that couples the functions of interacting cells. • Intercellular transfer is a general feature of homeodomain proteins (HPs) • HP secretion is a cell-context-sensitive event • Hydrophobic residues outside of the homeodomain support the secretion of HP Lee et al. evaluate capabilities of homeodomain proteins (HPs) for transfer between cells. They find that intercellular transfer is a general but cell-context-sensitive property of HP. Intercellular HP transfer can be an unconventional way for the cells to communicate with neighboring cells that associate structurally and functionally. [ABSTRACT FROM AUTHOR]

Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.