Background
HLA-A, -B, and -C are antigen-presenting cell-surface membrane proteins that play fundamental roles in the immune response to intracellular pathogens, transplant rejection (including stem cell therapy), autoimmunity and cancer. While isolated expression of HLA-C by extravillous trophoblast has been well documented, HLA-A,-B,-C is usually considered to be co-dominantly, expressed on HLA I-positive cells in the mature individual. However, we have just shown that the HLA-A,-B,-C genes are indeed differentially regulated in several human stem cells (all studied to date). Thus, cell-surface expression of HLA-B and -C alleles is strongly down-regulated whereas expression of HLA-A alleles remain high in stem cells. In contrast, HLA-A, -B and -C are equally expressed in blood leukocytes – the cells far most studied in this respect. The repressed HLA-B and -C proteins can be strongly up-regulated by interferon-gamma (IFN), a cytokine involved in the inflammatory response. Since different HLA alleles have variable affinities for intracellularly-generated peptides, the lack of HLA-B and -C expression can influence antigen presentation and the resulting immune response. Because we have demonstrated that the mRNA copy numbers of HLA-A,-B and -C are all similar in basal conditions in stem cells, and the IFNgamma-dependent mRNA and protein induction kinetics are similar, we hypothesize that the major contributor to repression of HLA-B and -C in stem cells during basal, non-induced conditions is a post-transcriptional mechanism leading to translational attenuation in stem cells.
Significance
HLA-A, -B, and -C play fundamental roles in the immune response to intracellular pathogens, transplant rejection (including stem cell therapy) and susceptibility to natural killer cell cytotoxicity. Some cells become stimulated to express HLA-A,-B,-C in response to inflammation, but do not express them constitutively. Many questions arise as to why some cells express HLA class I constitutively, and other cells do not, without becoming NK targets.
Aim
The objective of this proposal is to characterize the HLA-A and HLA-B regulatory regions to elucidate the molecular mechanism(s) that lead to post-transcriptional basal repression of HLA-B in human stem cells, and to constitutive expression of HLA-A and HLA-B in lymphocytes.