Abstract
To establish a healthy pregnancy, maternal immune cells must tolerate fetal allo-antigens and remain competent to respond to infections both systemically and in placental tissues. Extravillous trophoblasts (EVT) are the most invasive cells of extra-embryonic origin to invade uterine tissues and express polymorphic Human Leucocyte Antigen-C (HLA-C) of both maternal and paternal origin. Thus, HLA-C is a key molecule that can elicit allogeneic immune responses by maternal T and NK cells and for which maternal-fetal immune tolerance needs to be established. HLA-C is also the only classical MHC molecule expressed by EVT that can present a wide variety of peptides to maternal memory T cells and establish protective immunity. The expression of paternal HLA-C by EVT provides a target for maternal NK and T cells, whereas HLA-C expression levels may influence how this response is shaped. This dual function of HLA-C requires tight transcriptional regulation of its expression to balance induction of tolerance and immunity. Here, we critically review new insights into: (i) the mechanisms controlling expression of HLA-C by EVT, (ii) the mechanisms by which decidual NK cells, effector T cells and regulatory T cells recognize HLA-C allo-antigens, and (iii) immune recognition of pathogen derived antigens in context of HLA-C.
Highlights
Human Leukocyte Antigen-C (HLA-C) was first discovered by antigen-antibody analysis in the early 1970s [1], but its history started ∼10 million years ago on the precursor of the polygenic and polymorphic segment of human chromosome 6, which encodes the Major Histocompatibility Complex (MHC) molecules
HLA-C is a major determinant for NK cell activity [6, 7] and in 1983 a first report demonstrated the importance of HLA-C in pregnancy and placentation [8]
We critically discuss new insights into: (i) the mechanisms controlling the expression of HLA-C in the absence of HLA-A and HLA-B expression by placental extravillous trophoblasts (EVT); (ii) the mechanisms by which decidual NK cells, effector T cells and regulatory T cells recognize paternal HLA-C allo-antigens during pregnancy and its relevance in the development of pregnancy complications; and (iii) discuss
Summary
Human Leukocyte Antigen-C (HLA-C) was first discovered by antigen-antibody analysis in the early 1970s [1], but its history started ∼10 million years ago on the precursor of the polygenic and polymorphic segment of human chromosome 6, which encodes the Major Histocompatibility Complex (MHC) molecules. Variations in HLA-C cell surface expression levels have been shown to influence the efficacy of cellular immune responses to viral-, allo- and self-antigens [10, 11, 22]. While the expression of a polymorphic paternally inherited HLAC antigen by EVT provides a target for maternal NK cells and T cells to recognize and respond to, the HLA-C cell surface expression levels influence how this response is shaped.
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