Journal Article

HLA-B and HLA-C Differ in Their Nanoscale Organization at Cell Surfaces

Kennedy, Philippa R., Davis, Daniel M., Williamson, David J., Barthen, Charlotte

2019

Overview

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. We also found that the organization of HLA class I proteins varied with cell type. T cells exhibited a particularly clustered organization of HLA class I while B cells expressed a more uniform distribution. In summary, HLA class I variants are organized differently in the cell surface membrane which may impact their functions.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acquired immune deficiency syndrome / AIDS / Allotypes / Amino Acid Sequence / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Cell Membrane - metabolism / Cell membranes / Cell surface / Cysteine - chemistry / Fluorescent Antibody Technique / Gene Expression / Histocompatibility antigen HLA / HIV / HLA class I / HLA-B / HLA-B Antigens - chemistry / HLA-B Antigens - genetics / HLA-B Antigens - immunology / HLA-B Antigens - metabolism / HLA-C / HLA-C Antigens - chemistry / HLA-C Antigens - genetics / HLA-C Antigens - immunology / HLA-C Antigens - metabolism / Human immunodeficiency virus / Humans / Immunoglobulin-like receptors / Immunoglobulins / Immunological Synapses - immunology / Immunological Synapses - metabolism / Immunology / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Ligands / Lymphocytes / Lymphocytes B / Lymphocytes T / membrane / Microscopy / Mutation / nanoscale / Peptides / Potassium channels (inwardly-rectifying) / Protein Binding / super-resolution / T cell receptors