HLA-E EXPRESSION AND FUNCTION

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The class Ib HLA genes, HLA-E, -F, and -G, are less variable and have more limited tissue distribution than the class Ia genes. Because of these features they are considered either to have functions more specialized than the class Ia genes, which are as yet unknown, or instead to be non-functional. Recently, however, part of my thesis work included evidence for selection acting on at least one class Ib gene, HLA-E. This would imply that HLA-E is functional and this function needs to be determined. Preliminary functional studies of HLA-E have already verified that it binds peptides and indicate that it interacts with receptors on natural killer (NK) cells. The goals of this research are to increase current understanding of what the function of HLA-E may be by determining on which tissues its protein is expressed, what peptides it binds in vivo, and by looking for functional differences between alleles, a possibility suggested by previous selection studies. The first aim will be achieved by immunohistochemical staining and FACS analysis using monoclonal antibodies specific for the HLA-E protein recently developed in Dr. Geraghty's laboratory. Determination of the peptides bound by HLA-E will be done by mass spectrometry. The next aim, testing for functional differences between HLA-E alleles, will be accomplished by determining whether they bind different repertoires of peptides and if they are differentially recognized by NK cells. This research is important in a clinical context since HLA-E is ubiquitously expressed and may play a role in the outcome of marrow transplants.