Homotypic and heterotypic in cis associations of MHC class I molecules at the cell surface

Abstract

Through the presentation of peptide antigens to cytotoxic T lymphocytes, major histocompatibility complex (MHC) class I molecules mediate the adaptive immune response against tumors and viruses. Additional non-immunological functions include the heterotypic association of class I molecules with cell surface receptors, regulating their activities by unknown mechanisms. Also, homotypic associations resulting in class I dimers and oligomers - of unknown function - have been related to pathological outcomes. In this review, we provide an overview of the current knowledge about the occurrence, biochemical nature, and dynamics of homotypic and heterotypic associations of class I molecules at the cell surface with special focus on the molecular species that take part in the complexes and on the evidence that supports novel biological roles for class I molecules. We show that both heterotypic and homotypic class I associations reported in the literature describe not one but several kinds of oligomers with distinctive stoichiometry and biochemical properties.

Keywords: Closed conformers; Dimers; Empty conformers; Free heavy chain; Heterotypic associations; Homotypic associations; MHC class I; Non-covalent associations; Oligomers; Open conformers.

Graphical abstract

Fig. 1

Known species of MHC class I monomers and dimers. A, Schematic representation of the different molecular species of class I molecules (HβP, Hβ and H) found at the cell surface. P: antigenic peptide; H: class I transmembrane heavy chain; β: beta-2 microglobulin. B, Non-covalent homotypic associations between class I species (HβP/HβP, HβP/H and H/H) of the same or different allotypes (Table 1). C, Covalently bound class I dimers. For those dimers formed between free heavy chains (H), the same or different allotypes might be involved, and the disulfide bond links the extracellular domains (H-H) or the cytosolic domains (H.H). Covalent dimers of HβP species (HβP-HβP) were only reported for HLA-G (Table 1). D, Example of heterotypic association. The non-covalent interaction between HβP or H with the insulin receptor (IR) is depicted as an example. The structure of the IR is simplified and does not reflect the actual structure of the receptor. Different interacting partners were described in the literature (Table 2). For clarity, only dimeric associations of a single allotype are shown.