Variations in HLA-B cell surface expression, half-life and extracellular antigen receptivity

Most cells in the body make proteins called human leukocyte antigen class I (or HLA-I). These proteins sit on the cell surface, where they help the immune system distinguish between healthy and diseased cells. A groove in each HLA-I protein holds a fragment of a protein chain, called a peptide, from inside the cell. In healthy cells, all the peptides come from normal proteins. Yet in diseased or infected cells, the peptides may come from abnormal or foreign proteins – those encoded by viruses, for example. When the immune system sees these abnormal peptides, it responds by killing the cell. Across the human population, there are thousands of types of HLA-I, each able to carry a different set of peptides. Any individual person can only make a maximum of six types of the HLA-I, meaning we each show a different combination of peptides to our immune cells. This difference will change the way different people respond to the same disease. Before a peptide can be assembled into HLA-I, it must be moved to the correct part of the cell by a transporter known as TAP. This transport favors peptides with certain characteristics, but these characteristics do not always match the preferences of the individual's HLA-I proteins. For example, TAP is less likely to transport peptides where the second building block in the chain is a proline, but these peptides will still fit into the binding grooves of some HLA-I variants. Here, Yarzabek, Zaitouna, Olson et al. obtained blood from healthy human donors to answer questions about what happens when TAP and HLA-I have different preferences. Specifically, how many HLA-I molecules reach the surface, how long do they last, and which peptides do they carry? This analysis revealed that, when there was a mismatch between HLA-I and TAP, the amount of some HLA-I types on the surface of white blood cells called lymphocytes dropped. These HLA-I types were also able to pick up new peptides from their environment, indicating that some HLA-I were at the surface of the cell without a peptide. The role of these empty HLA-I remains to be fully defined. The reverse was true for other white blood cells called monocytes; HLA-I variants that were mismatched with TAP became more abundant on the cell surface. Monocytes also had more HLA-I molecules inside and did not pick up peptides from the environment. This suggests that monocytes may load peptides via new pathways, filling grooves left empty in lymphocytes, although other mechanisms might also explain the differences between the two types of white blood cells. Taken together, the findings reveal that HLA-I on the surface of cells depends on both the type of HLA-I and the type of immune cell. HLA-I proteins play a key role in the immune system’s ability to recognize and kill diseased cells. A better knowledge of how HLA-I variants differ could help us to understand why people respond differently to the same disease. A better grasp of HLA-I could in the future lead to improved drug and vaccine design.