Conformational sensing of major histocompatibility complex (MHC) class I molecules by immune receptors and intracellular assembly factors

Abstract

Major histocompatibility complex class I (MHC-I) molecules play a critical role in both innate and adaptive immune responses. The heterodimeric complex of a polymorphic MHC-I heavy chain and a conserved light chain binds to a diverse set of peptides which are presented at the cell surface. Peptide-free (empty) versions of MHC-I molecules are typically retained intracellularly due to their low stability and bound by endoplasmic reticulum chaperones and assembly factors. However, emerging evidence suggests that at least some MHC-I allotypes are relatively stable and detectable at the cell-surface as peptide-deficient conformers, under some conditions. Such MHC-I conformers interact with multiple immune receptors to mediate various immunological functions. Furthermore, conformational sensing of MHC-I molecules by intracellular assembly factors and endoplasmic reticulum chaperones influences the peptide repertoire, with profound consequences for immunity. In this review, we discuss recent advances relating to MHC-I conformational variations and their pathophysiological implications.

Figure 1.

Structure and interaction sites of MHC-I. MHC-I is composed of a heavy chain (green) that has three domains (α1, α2 and α3), a light chain β₂m (violet), and a peptide (red). The recognition sites of TCR, KIR, CD8, LIR1/LIR2 and tapasin/TAPBPR are indicated. There are two major tapasin/TAPBPR binding regions on MHC-I. The crystal structure of HLA-B*5701 in complex with peptide LSSPVTKSF (pdb: 2rfx) is used and the figure was generated with PyMOL.

Figure 2.

Structural alignments of TAPBPR-associated (red) and peptide-filled (blue) MHC-I molecules show significant movements of both the α1-α2 and α3 domains. (A) The structure of H2-D^d-TAPBPR complex (5wer) was superimposed onto H2-D^d with a 10mer peptide (5weu). TAPBPR was omitted to compare the conformations of H2-D^d in peptide and TAPBPR-bound forms. (B) α1 and α2 domain of the structures shown in A. (C) α3 domain of the structures shown in A, with the CD8 binding loop indicated. The figure was generated with PyMOL.

Figure 3.

Interactions between MHC-I and CD8 provide co-receptor-based synergy for receptors of CD8⁺ T cells and NK cells (A and B), and enhanced binding between CD8 and peptide-free versions of some MHC-I allotypes contributes to increased adhesion between CD8-expressing cells and MHC-I-expressing target cells (C). (A) CD8αβ heterodimers are co-receptors for TCR recognizing cognate pHLA-I. The structure of TCR–HLA-A*02:01 complex (PDB: 5c0a) was superimposed with H2-D^d- CD8αβ (PDB: 3dmm) by aligning HLA-A*02:01 and H2-D^d, and H2-D^d was then deleted to generate a model for the TCR–HLA-A*02:01-CD8αβ complex. (B) A model for the complex between CD8αα and KIR3DL1 of NK cells with HLA-I of target cells, wherein CD8αα has co-receptor function in NK cells, similar to that for CD8αβ in T cells. The structure of KIR3DL1–HLA-B*57:01 complex (PDB: 3vh8) was superimposed onto HLA-A*02:01-CD8αα (PDB: 1akj) by aligning HLA-B*57:01 and HLA-A*02:01, followed by deletion of HLA-A*02:01 to generate a model for the KIR3DL1-HLA-B*57:01-CD8αα complex. (C) CD8 has been shown to preferentially bind to the empty version of HLA-B*35:01 relative to specific peptide-filled versions. To depict this type of interaction, peptide was deleted from the structure of H2-D^d-CD8αβ (PDB: 3dmm) to model a peptide-free MHC-I allotype binding to CD8αβ of CD8⁺ T cells. PyMOL was used to visualize the structures of HLA-I and its receptors.