The immunoregulatory role of HLA-F in human diseases

Abstract

HLA-F is a non classical HLA-I molecule that can be a strong activating trigger for highly cytotoxic natural killer (NK) cells when upregulated on virus-infected target cells. HLA-F surface expression is tightly regulated and has been described upon activation on lymphocytes under healthy conditions. In pathologies, HLA-F surface expression has been described in various viral diseases, autoimmune diseases and cancers. HLA-F expression in tissue and the factors inducing its upregulation at the cell surface are to date unclear but are likely important given its potential to trigger cytotoxic immune responses against stressed tissues. Human immunodeficiency virus 1 (HIV-1) is a viral infection with major global health impact and achieving long-term immune control of HIV-1 infection is currently a strong focus of research efforts in advancing HIV-1 patient treatment. Autoimmune hepatitis (AIH), an autoimmune liver disease, is lacking targeted treatment options apart from unspecific immunosuppression due to the missing understanding of underlying mechanisms driving disease. In this thesis, the surface expression of HLA-F, the stress ligands NKG2DL and their receptors on NK cells were profiled on therapy naïve HIV positive individuals. The upregulation of HLA-F as a marker of ongoing immune activation in HIV-1 infection was detected, along with NK cell phenotypic alterations. In vitro studies of uninfected activated CD4 T cell-killing by NK cells, a potential mechanism of immunomodulatory regulation by NK cells in HIV-1 infection, revealed that the HLA-F:KIR3DS1 axis is possibly implicated in this mechanism in combination with the NKG2DL:NKG2DL axis. The stimulation of hepatoma cell lines and human hepatocyte organoids derived from AIH patient samples revealed that HLA-F surface expression in hepatic tissue is potentially driven by a two-step mechanism via pro-inflammatory stimulation, explaining the wide tissue expression of HLA-F during inflammatory diseases. HLA-F remains an enigmatic stress ligand with a clear link to various human diseases, rendering it interesting as a therapeutic target.