HLA-B polymorphisms and intracellular assembly modes

https://doi.org/10.1016/j.molimm.2015.07.007Get rights and content

Highlights

  • Peptide-deficient forms of HLA-B molecules have varying stabilities.

  • HLA-B molecules can assemble via tapasin-dependent or tapasin-independent routes.

  • Assembly modes may confer selective immune advantages for CTL or NK recognition.

Abstract

Human leukocyte antigen (HLA) class I molecules are ligands for antigen receptors of cytotoxic T cells (CTL) and inhibitory receptors of natural killer (NK) cells. The high degree of HLA class I polymorphism allows for the selection of distinct and diverse sets of antigenic peptide ligands for presentation to CTL. The extensive polymorphisms of the HLA class I genes also result in large variations in their intracellular folding and assembly characteristics. Recent findings indicate that North American HLA-B variants differ significantly in the stabilities of their peptide-deficient forms and in the requirements for the endoplasmic reticulum (ER)-resident factor tapasin for proper assembly. In HIV-infected individuals, the presence of tapasin-independent HLA-B allotypes links to more rapid progression to death. Further studies are important to better understand how the intrinsic structural characteristics of HLA class I folding intermediates affect immune responses mediated by CTL and NK cells.

Section snippets

MHC class I molecules as ligands for cytotoxic T cell (CTL) and natural killer (NK) cell receptors

Major histocompatibility complex (MHC) class I molecules are ligands for antigen receptors of CD8+ CTL (Bjorkman, 1997, Rossjohn et al., 2014) and for inhibitory receptors of natural killer (NK) cells (Parham and Moffett, 2013). In a normal healthy cell, MHC class I heavy chains and light chains (β2-microglobulin; β2m) form heterodimers that bind short peptides derived from self-proteins. In cells infected with an intracellular pathogen or in cancer cells, a subset of the cellular peptides

MHC class I assembly in the ER

The assembly of MHC class I molecules occurs within the ER of cells, and involves the assembly factors TAP (transporter associated with antigen presentation) (Mayerhofer and Tampe, 2015) and tapasin (Blum et al., 2013), that are also encoded within the MHC gene complex, that includes the MHC class I heavy chain genes. In the endogenous pathway of antigen presentation, peptides that derive from cytosolic proteolysis are transported into the ER by TAP. TAP is comprised of two subunits, TAP1 and

MHC polymorphisms and assembly variations

Human TAP and tapasin sequences have no known functional polymorphisms. Rat TAP2 and chicken TAP1 and TAP2 sequences have functional polymorphisms that are known to affect peptide transport specificity. Chicken MHC haplotypes have TAP1, TAP2 and tapasin allele variants that are optimally configured for the transport and binding of peptide sequences relevant to the encoded MHC class I (Kaufman, 2015). Further studies of such functional polymorphisms are expected to provide insights into peptide

HLA-B polymorphisms and AIDS outcomes

The extreme polymorphism of the MHC class I molecules reflects evolutionary adaptations of T and NK cell responses to pathogens, in addition to NK cell functions during reproduction (Parham and Moffett, 2013). Since different combinations of HLA-A, B and C variants are present within individuals in a population, distinct sets of pathogen-derived peptides are presented during infections, resulting in the induction of CTL responses with distinct specificities. Thus, it might be expected that HLA

Acknowledgements

This work was funded by a NIH grant AI044115 (to MR). This work was supported in part by the University of Michigan Medical School Fast Forward Protein Folding Diseases Initiative.

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