The Role of HLA-Class I Heavy-Chain Interactions with Killer-Cell Immunoglobulin-Like Receptors in Immune Regulation

HLA-class I molecules form trimeric complexes (pMHC) of peptides, class I heavy chains, and β2microglobulins (β2m) that regulate immune responses by binding to T cells and other immune receptors. B2m-free class I heavy chains (FHCs) form on cells either as a consequence of the natural turnover of pMHC or, in the case of HLA-F, are expressed without β2m. Distinct characteristics of certain HLA-class I members, such as HLA-B27 and HLA-F, stabilize these forms facilitating interactions with immune receptors. FHC forms of HLA-class I have been shown to bind to killer-cell immunoglobulin-like receptor (KIR) family members. The binding of FHC forms to KIR3DL2 regulates natural killer (NK) and T-cell functiona and promotes lymphocyte survival. KIR3DL2 binding to B27 FHC dimers has been implicated in the pathogenesis of spondyloarthritis (SpA). KIR3DL2 binding FHC forms could also play a role in immune cell recognition of certain tumors and in regulation of immune homeostasis at the maternal-fetal interface. Here, I review the evidence for the functional interaction of cell surface HLA-class I FHCs with KIR family members. I also discuss the relevance of these interactions in immune homeostasis and immune dysfunction in diseases in which FHC-binding KIRs have been implicated.