1. HLA-B and HLA-C differ in their nanoscale organization at cell surfaces
- Author
-
Kennedy, PR, Barthen, C, Williamson, DJ, and Davis, DM
- Subjects
EXPRESSION ,HLA-B ,HLA-C ,Immunological Synapses ,Immunology ,INHIBITION ,Fluorescent Antibody Technique ,Gene Expression ,super-resolution ,HLA-C Antigens ,IMMUNITY ,CLASS-I PROTEINS ,ESCAPE ,RECEPTOR NANOCLUSTERS ,Humans ,NK cell ,Amino Acid Sequence ,Cysteine ,membrane ,Original Research ,GAG ,B-Lymphocytes ,Science & Technology ,COMPLEX ,MUTATIONS ,TRANSMEMBRANE SEQUENCE ,Cell Membrane ,immune synapse ,HLA class I ,nanoscale ,Killer Cells, Natural ,HLA-B Antigens ,Life Sciences & Biomedicine ,Protein Binding - Abstract
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.
- Published
- 2019