Tcel receptor kinase7/1/2023 There are two classes of MHC molecules that are involved in antigen presentation: MHC class I and MHC class II. MHC molecules play an important role in the communication between the innate and adaptive immune system. MHC-I Function in T Cell Activation and NK Cell Regulation Here, we review the evidence for the alternative role of MHC-I as reverse signaling molecules across immune and non-immune cells. Furthermore, reverse MHC-I signaling has been investigated in the context of viral and bacterial infections ( 6, 9), transplantation immunity ( 10), malignancies ( 11), and brain development ( 12). MHC-I reverse signaling has been observed in multiple cell types, ranging from immune cells, such as macrophages, NK cells, T cells, and B cells, to non-immune cells like endothelial and smooth muscle cells ( 7, 8). Multiple studies have shown that reverse MHC-I signaling can influence processes like cell activation, proliferation, maturation, cytotoxicity, and migration, or even lead to cell anergy and apoptosis ( 3, 5, 6). In this process, here referred to as reverse MHC-I signaling, ligation of MHC molecules can lead to signal-transduction and cell regulatory effects in the APC ( 3, 4). Moreover, MHC-I molecules are important immune regulators, since their expression levels regulate activation of natural killer (NK) cells ( 1, 2).Īn underappreciated function of MHC-I molecules is their ability to act as signaling receptors. Additionally, in the case of professional antigen presenting cells (APCs), MHC-I can also present exogenous antigens through a process called antigen cross-presentation. Major histocompatibility complex class I (MHC-I) molecules are present on all nucleated cells and are classically known for presenting peptides derived from endogenous antigens to cytotoxic CD8 + T lymphocytes (CTL). Thereby, reverse MHC-I signaling is a potential target for therapies against viral and bacterial infections, cancer immunotherapies and management of organ transplantation outcomes. For other cell types, the role of reverse MHC-I signaling is less clear, since aspects like the in vivo relevance, natural MHC-I ligands and the extended downstream pathways are not fully known.The existing evidence, however, suggests that reverse MHC-I signaling is involved in the regulation of the defense against bacterial and viral infections and against malignancies. For endothelial and smooth muscle cells, the in vivo relevance of reverse MHC-I signaling has been established, namely in the context of adverse effects after tissue transplantation. Signaling molecules like RAC-alpha serine/threonine-protein kinase (Akt1), extracellular signal-regulated kinases 1/2 (ERK1/2), and nuclear factor- κB (NF- κB) were common signaling molecules activated upon MHC-I ligation in multiple cell types. Here, we provide an overview of studies showing the signaling pathways and cell outcomes upon MHC-I stimulation in various immune and non-immune cells. In the case of MHC-I, reverse signaling can have several outcomes, including apoptosis, migration, induced or reduced proliferation and cytotoxicity towards target cells. In this process, here referred to as reverse MHC class I (MHC-I) signaling, ligation of MHC molecules can lead to signal-transduction and cell regulatory effects in the antigen presenting cell. However, much less appreciated is the fact that MHC molecules can also act as signaling receptors. Major histocompatibility complex (MHC) molecules are well-known for their role in antigen (cross-) presentation, thereby functioning as key players in the communication between immune cells, for example dendritic cells (DCs) and T cells, or immune cells and their targets, such as T cells and virus-infected or tumor cells. 2Department of Molecular Microbiology and Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands.1Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.Meesters 1, Geert van den Bogaart 1,2 and Natalia H.
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