Abstract
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. However, much less appreciated is the fact that MHC molecules can also act as signaling receptors. 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. In the case of MHC-I, reverse signaling can have several outcomes, including apoptosis, migration, induced or reduced proliferation and cytotoxicity towards target cells. 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. 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. 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. 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. Thereby, reverse MHC-I signaling is a potential target for therapies against viral and bacterial infections, cancer immunotherapies and management of organ transplantation outcomes.
Highlights
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)
Based on experiments using MHC class I ligation with antibodies, this study proposed a mechanism in which the Src homology 2 (SH2) domain of the tyrosine kinase Fps interacts with a phosphorylated tyrosine site in the cytoplasmic domain of MHCI, leading to Fps activation (Figure 2) [9]
MHC-I signaling has been shown to affect cell apoptosis, activation, proliferation, cytotoxicity and migration in many cell types, including immune cells, epithelial cells and tumor cells [3, 5, 6]. Because of these broad actions, reverse MHC-I signaling is relevant to several fields, including research into viral and bacterial infections [6, 9], transplantation outcomes [9] and malignancies [11]
Summary
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). The classical MHC-I molecules (MHC-Ia) are responsible for activating CD8+ T cells and correspond to a-chains that are expressed at high levels and are highly polymorphic to allow for increased variability of peptide binding sites In humans, these correspond to the HLA-A, HLA-B, and HLA-C genes, and in mice, these genes are H-2K, H-2D and H2L. Reverse MHC-I signaling may regulate the activity of macrophages to prevent an excessive response and damage [9] This effect could be induced after interaction with the TCR on CD8+ T cells [9], but potentially receptors on NK-cells, such as KIR receptors or C-type lectin-like receptors like Ly49 [38]. In comparison to the other cell types discussed in this review, reverse MHC-I signaling has been understudied in DCs (Table 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
