Immunogenetics

, Volume 57, Issue 5, pp 315–325

A biochemical and structural analysis of genetic diversity within the HLA-A*11 subtype

Original Paper

DOI: 10.1007/s00251-005-0801-7

Cite this article as:
Li, L., Chen, W. & Bouvier, M. Immunogenetics (2005) 57: 315. doi:10.1007/s00251-005-0801-7

Abstract

The HLA-A*11 subtype includes 17 naturally occurring variants (-A*1101 to -A*1117) distributed among different ethnic groups worldwide. At present, only HLA-A*1101 has been characterized at the molecular, structural, and immunological level. Developing similar knowledge on other HLA-A*11 alleles is highly important for bone marrow and graft transplantation. This is also important to better understand disease linkages within the HLA-A*11 subtype given that HLA-A*11 molecules are associated with resistance to acquisition of HIV-1 infection and various autoimmune diseases. To broaden our understanding of HLA-A*11 molecules, we have determined the impact of natural polymorphism on the peptide-binding properties of several HLA-A*11 molecules: -A*1103, -A*1106, -A*1108, -A*1110, -A*1111, and -A*1114. We used an approach that combines data from thermal stability studies of recombinant, soluble forms of these molecules in complex with HIV-1 peptides, together with a detailed structural analysis of the resulting HLA-A*11 molecule/peptide complexes based on crystal and molecular model structures. Our analysis shows that natural polymorphism within the HLA-A*11 subtype is distributed along the α1 and α2 helices of the peptide-binding groove, in marked contrast to the pattern of polymorphism in HLA-A*2 and HLA-B*27 subtypes. Natural polymorphism greatly altered the abilities of individual -A*11 molecules to form stable complexes with HIV-1 peptides. In comparison to -A*1101, natural polymorphism altered the peptide-presenting properties of -A*1103, -A*1108, and -A*1114 and has the potential to affect the peptide-selecting properties of -A*1106, -A*1110, and -A*1111 as well. Overall, our findings suggest that HLA-A*11 molecules may stimulate alloreactive CD8+ cytotoxic T-cell responses.

Keywords

Alloreactivity Antigen selection and presentation HLA-A*11 alleles Natural polymorphism Structural analysis 

Abbreviations

β2m

β2-microglobulin

CD

circular dichroism

CTL

cytotoxic T lymphocyte

EBV

Epstein–Barr virus

ER

endoplasmic reticulum

GVH

graft-vs-host

HLA

human leukocyte antigen

MD

molecular dynamics

P

position

RT

reverse transcriptase

Tm

midpoint temperature

TCR

T-cell receptor

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.School of PharmacyUniversity of ConnecticutStorrsUSA