Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function

The immune system keeps tabs on everything that happens in our body, looking for potential signs of threat. To alert it to any problems, almost every cell produces specific proteins on its surface called human leukocyte antigens class I, or HLA-I for short. These HLA-I molecules are bound to small protein fragments called peptides that have been exported from within the cell and are presented to the cells of the immune system for scanning. When cells are healthy, the peptides all stem from normal proteins. But, if the cell has become infected or cancerous, it contains foreign or abnormal peptides. Some of the HLA-I molecules, however, are empty. These antigens are unstable, and their role is unclear. Now, Geng et al. investigated this further by studying blood samples from healthy donors. The experiments revealed that empty HLA-I molecules help specialized cells of the immune system, the killer T cells, to bind to the antigens, improving their killing ability. It is known that these T cells recognize and bind to the antigens through two receptor proteins, one of which is called CD8. It was known that when HLA-I molecules carry a peptide, only a small fraction of T cells with a matching receptor can bind. However, Geng et al. found that when HLA-Is were empty, a much larger proportion of the T cells was able to bind to antigens. This indicates that CD8 ‘prefers’ to attach to empty HLA-Is, maybe because binding sites are more accessible. CD8 also enhances the binding between the T cells and the antigen. Empty HLA-Is did not directly activate the T cells but did enhance their immune response. When both full and empty HLA-I were present, the T cells were even more effective at killing their targets. Understanding how killer T cells work is essential for the development of immunotherapies – treatments that help to boost the immune system to fight infections and cancer. Increasing the number of empty HLA-I molecules on cancer or infected cells could enhance T cell killing.