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Front. Immunol. | doi: 10.3389/fimmu.2019.00061

HLA-B and HLA-C differ in their nanoscale organization at cell surfaces

Philippa R. Kennedy1, Charlotte Barthen1, 2,  David J. Williamson1 and  Daniel M. Davis1*
  • 1Manchester Collaborative Centre for Inflammation Research, University of Manchester, United Kingdom
  • 2Division of Cell and Molecular Biology, Imperial College London, United Kingdom

The particular HLA class I variants an individual carries influences their resistance and susceptibility to a multitude of diseases. Expression level and variation in the peptide binding region correlates with, for example, a person’s progression to AIDS after HIV infection. One factor which has not yet been addressed is whether or not different HLA class I proteins organize differently in the cell membrane on a nanoscale. Here, we examined the organization of three HLA-B allotypes (B*2705, B*5301 and B*5701) and two HLA-C allotypes (C*0602 and C*0702) in the membrane of 721.221 cells which otherwise lack expression of HLA-B or HLA-C. All these allotypes are ligands for the T cell receptor and leukocyte immunoglobulin-like receptors, but additionally, the HLA-B allotypes are ligands for the killer-cell immunoglobulin-like receptor family member KIR3DL1, HLA-C*0602 is a ligand for KIR2DL1, and HLA-C*0702 is a ligand for KIR2DL2/3. Using super-resolution microscopy, we found that both HLA-B and HLA-C formed more clusters and a greater proportion of HLA contributed to clusters, when expressed at lower levels. Thus, HLA class I organization is a covariate in genetic association studies of HLA class I expression level with disease progression. Surprisingly, we also found that HLA-C was more clustered than HLA-B when expression level was controlled. HLA-C consistently formed larger and more numerous clusters than HLA-B and a greater proportion of HLA-C contributed to clusters than for HLA-B. Thus, HLA class I variants are organized differently in the cell surface membrane which may impact their functions.

Keywords: HLA class I, membrane, nanoscale, super-resolution, HLA-B, HLA-C, immune synapse, NK cell

Received: 02 Nov 2018; Accepted: 11 Jan 2019.

Edited by:

Eric O. Long, National Institute of Allergy and Infectious Diseases (NIAID), United States

Reviewed by:

Paul J. Norman, University of Colorado Denver, United States
Markus Uhrberg, Heinrich Heine Universität Düsseldorf, Germany  

Copyright: © 2019 Kennedy, Barthen, Williamson and Davis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Daniel M. Davis, University of Manchester, Manchester Collaborative Centre for Inflammation Research, Manchester, M13 9PL, North East England, United Kingdom,