HLA-G and immune tolerance in pregnancy
Joan S. Hunt,*,1 Margaret G. Petroff,* Ramsey H. McIntire,* and Carole Ober†
*University of Kansas Medical Center, Kansas City, Kansas, USA; and †The University of Chicago, Chicago, Illinois, USA Multiple mechanisms underlie the surprising willingness of mothers to tolerate genetically different fetal tissues duringpregnancy. Chief among these is the choice of HLA-G, a gene with few alleles, rather than the highly polymorphic HLA-A and -B genes, for expression by the placental cells that interface directly with maternal blood and tissues. Novel aspects of this major histocompatibility complex class Ib gene include alternative splicing to permit production of membrane and soluble isoforms, deletions that dampenresponses to interferons, and a shortened cytoplasmic tail that affects expression at the cell surface. Placental cells migrating into the maternal uterus synthesize both membrane and soluble isoforms, which interact with inhibitory receptors on leukocytes such as ILT2 and ILT4. Cytotoxic T lymphocytes either die or reduce production of one of their major coreceptor/activator cell surface molecules,CD8; natural killer cells are immobilized and mononuclear phagocytes are programmed into suppressive modes characterized by high production of anti-inﬂammatory cytokines. The idea that placental HLA-G proteins facilitate semiallogeneic pregnancy by inhibiting maternal immune responses to foreign (paternal) antigens via these actions on immune cells is now well established, and the postulate that therecombinant counterparts of these proteins may be used as powerful tools for preventing immune rejection of transplanted organs is gaining in popularity.—Hunt, J. S., Petroff, M. G., McIntire, R. H., Ober, C. HLA-G and immune tolerance in pregnancy. FASEB J. 19, 681– 693 (2005)
tation antigens are late appearing; tolerance and immune privilege at the maternal-fetal interface arereadily identiﬁed. Three major principles emerging from these studies are that 1) multiple mechanisms provide protection, 2) both the fetus and the mother contribute to development and maintenance of the pregnant uterus as an immune privileged site, and 3) fetal factors drive changes in maternal immune responses. In this article, we ﬁrst brieﬂy discuss a number of conditions responsible for immuneprivilege and maternal tolerance for which scientiﬁc evidence is strong, then focus on a central feature—a unique capacity of placental cells to select speciﬁc genes within the major histocompatibility complex (MHC) for expression. We present evidence that this unique capacity for selection of speciﬁc MHC antigens, which in humans are called human leukocyte antigens (HLA), may be responsible in largepart for the reprogramming of local maternal immune responses that characterize successful semiallogeneic pregnancy. Strategies for protecting the semiallogeneic fetus from maternal graft rejection responses During pregnancy, the maternal immune system is clearly active, and under certain conditions may contribute to fetal damage/death. Well-deﬁned pathological processes include destruction offetal erythrocytes (Rh antigen, erythroblastosisis) and platelets (HPA-1 and -2, alloimmune thrombocytopenia) by maternal antibodies and infections of pregnancy, where activated macrophages secreting high levels of Th1-type cytokines alter the delicate cytokine balance at the maternal-fetal interface (2, 3). Yet even with a demonstrably active maternal immune system, mothers usually seemCorrespondence: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, 66160-7400 USA. E-mail: email@example.com Supported in part by grants from the National Institutes of Health to J.S.H. (HD26429, HD35859, and HD39878), to M.G.P. (HD045611), and to C.O. (HD21244). R.M. is supported by a fellowship from the Kansas University Medical Center Biomedical Research...