Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types

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.

Keywords: apoptosis; cell activation; dendritic cell; immunological synapse; migration; proliferation; reverse MHC class I signaling; tumor immune responses.

Figure 1

The antigen presenting role of MHC class I molecules and their structure. (A) The immunological synapse is a communication platform between a (professional) antigen-presenting cell and a T or NK cell. In the example presented here, MHC-I molecules on the surface of a dendritic cell (purple) present antigens (orange) for their recognition by the TCR of a CD8⁺ T cell (blue). CD8 acts as co-receptor of the TCR for the recognition of the MHC-I molecule. At the immunological synapse (red box), other molecules required for the engagement and modulation of the interaction are also recruited, such as adhesion molecules (LFA-1 and ICAM-I) and costimulatory molecules (CD80/86 and CD28). (B) MHC-I molecules are heterodimers composed of a heavy α chain (blue) and a light chain (β2-microglobulin) (gray). Most α chains are made up of two peptide binding domains (α1 and α2), and an Ig-like α3 domain recognized by CD8 molecules on T cells. Additionally, the α chain has a transmembrane and a short cytoplasmic tail (cyan). (C) The cytoplasmic regions of several classical and non-classical MHC-I α chains contain a tyrosine residue that can be phosphorylated. This phospho-tyrosine residue has been proposed to interact with signaling proteins and thus leads to reverse signaling. Here we present the cytoplasmic regions of human classical (MHC-Ia) and non-classical (MHC-Ib) α chains, and the classical mouse α chains. However, some of the multiple non-classical mouse α chains also contain this tyrosine residue.

Figure 2

Summary of reverse MHC-I signaling pathways in various cell types. Summary of the main reverse MHC-I signaling pathways in immune (A–D) and non-immune cells (E–H). Question marks indicate steps in the pathway that are still unknown. Interactions represented by solid lines were confirmed to participate in reverse MHC-I signaling, while the interaction represented with a dashed line in (E) represents the authors’ speculation. The asterisk symbol (*) indicates the antigen binding site of MHC-I. In the case of Endothelial cells (F), reverse MHC-I signaling has been well studied and only a brief overview is presented here. A more detailed description can be found in a review by Valenzuela and Reed, 2011 (5).