Mice homozygous for a beta 2-microglobulin gene disruption do not express any detectable beta 2-m protein. They express little if any functional major histocompatibility complex (MHC) class I antigen on the cell surface yet are fertile and apparently healthy. They show a normal distribution of gamma delta, CD4+8+ and CD4+8- T cells, but have no mature CD4-8+ T cells and are defective in CD4-8+ T cell-mediated cytotoxicity. Our results strongly support earlier evidence that MHC class I molecules are crucial for positive selection of T cell antigen receptor alpha beta+ CD4-8+ T cells in the thymus and call into question the non-immune functions that have been ascribed to MHC class I molecules.

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Maternal immunoglobulin G transmitted to the fetus or newborn provides humoral immunity for the first weeks of mammalian life. Fc receptors on intestinal epithelial cells of the neonatal rat (FcRn) mediate the uptake of IgG from milk. Affinity-purified FcRn is resolved by SDS-PAGE into components of relative molecular masses 45,000-53,000 (p51) and about 14,000 (p14). We report the identification of the smaller component as beta 2-microglobulin. Association of beta 2-microglobulin with p51 was confirmed by crosslinking in intestinal epithelial cell brush borders. We have cloned a cDNA encoding the presumptive Fc-binding subunit, p51, and its predicted primary structure has three extracellular domains and a transmembrane region which are all homologous to the corresponding domains of class I major histocompatibility complex (MHC) antigens. This is the first time a function has been assigned to an MHC antigen-related molecule.

IntroductionSteady-state levels of IgG in the blood of adult mice, and likely all mammals, depend on IgG catabolism mediated in part by the MHC class I-related Fc receptor, FcRn (1). FcRn also mediates vectorial transport of IgG across certain epithelial barriers. In suckling mice and rats, intestinal absorption of maternal IgG from breast milk into the systemic circulation depends on FcRn (2). In humans, maternofetal transfer of IgG across the placenta also likely depends on FcRn (3). Thus, FcRn plays critical and well-documented roles in the regulation of IgG metabolism in adults and in the acquisition of humoral immunity in early life. These effects on the physiology of IgG in vivo result from the action of FcRn as an intracellular trafficking receptor (4).FcRn has been cloned from the rat, mouse, and human. The molecule is expressed as a heterodimer composed of a glycosylated heavy (α) chain (51 kDa in rodents and 40-45 kDa in humans) associated noncovalently with β2-microglobulin (β2M) (5). Binding of IgG to FcRn requires contact between solvent-exposed peptide sequences in the CH2 and CH3 domains of IgG and the α1 and α2 domains of FcRn, together with a single contact site in β2M (6-11). A hallmark of FcRn interaction with IgG is its pH dependence, showing high-affinity binding at acidic pH (pH ≤ 6.5) and weak or no binding at neutral pH (pH ≥ 7.0) (12, 13). FcRn is the only Fcγ receptor that exhibits MHC class I structure, and the only Fcγ receptor to exhibit pH dependency in ligand binding.The function of FcRn in the intestine of suckling mice and rats has been well documented (14). In neonatal mice and rats, FcRn is expressed at high levels by intestinal epithelial cells and mediates absorption of IgG by receptor-mediated transcytosis. FcRn expression in the neonatal rodent is developmentally downregulated, resulting in nearly complete loss of intestinal FcRn at the time of weaning (15)(16)(17) The MHC class I-related Fc receptor, FcRn, mediates the intestinal absorption of maternal IgG in neonatal rodents and the transplacental transport of maternal IgG in humans by receptor-mediated transcytosis. In mice and rats, expression of FcRn in intestinal epithelial cells is limited to the suckling period. We have recently observed, however, clear expression of FcRn in the adult human intestine, suggesting a function for FcRn in intestinal IgG transport beyond neonatal life in humans. We tested this hypothesis using the polarized human intestinal T84 cell line as a model epithelium. Immunocytochemical data show that FcRn is present in T84 cells in a punctate apical pattern similar to that found in human small intestinal enterocytes. Solute flux studies show that FcRn transports IgG across T84 monolayers by receptor-mediated transcytosis. Transport is bidirectional, specific for FcRn, and dependent upon endosomal acidification. These data define a novel bidirectional mechanism of IgG transport across epithelial barriers that predicts an important effect of FcRn on IgG function in immune surveillance and host de...

SummaryThe acquisition of maternal antibodies is critical for immunologic defense of the newborn. In humans, maternal IgG is actively transported across the placenta. The receptor responsible for this transport has not been identified definitively. We report the isolation from a placental cDNA library of clones encoding the oe-chain of an immunoglobulin G (IgG)-Fc receptor (hFcRn) that resembles a class I major histocompatibility complex antigen. The DNA and predicted amino acid sequences are very similar to those of the neonatal rat and mouse intestinal Fc receptors, rFcRn and mFcP, n. These receptors mediate transport of maternal IgG from milk to the bloodstream of the suckling rat or mouse. Like rat and mouse FcRn, hFcR_n binds IgG preferentially at low pH, which may imply that IgG binds hFcRn in an acidic intracellular compartment during transport across the placenta.

SUMMARYMaternal IgG is transferred to the suckling mouse and rat through a major histocompatibility complex (MHC ) class I-related Fc receptor (FcRn) on the brush border of the proximal small intestine. We have previously described a site on the epithelial surface of the human fetal intestine with IgG binding characteristics similar to FcRn. We report here the identification by reverse transcriptase polymerase chain reaction amplification and sequencing of the human orthologue of rat and mouse FcRn in tissue obtained from human fetal and adult intestine. FcRn protein was detected in adult human intestine by western blot. Immunohistochemical studies of sections of human intestine show that the FcRn is localized mostly to the epithelial cells, where it is in the apical region. These data suggest that the binding of IgG previously seen in the fetal intestine is due to the presence of FcRn. Potential roles for this MHC class I-like Fc receptor in the human intestine include the transfer of passive immunity, induction of oral tolerance, and immunosurveillance.

The three-dimensional structure of the rat neonatal Fc receptor (FcRn) is similar to the structure of molecules of the major histocompatibility complex (MHC). The counterpart of the MHC peptide-binding site is closed in FcRn, making the FcRn groove incapable of binding peptides. A dimer of FcRn heterodimers seen in the crystals may represent a receptor dimer that forms when the Fc portion of a single immunoglobulin binds. An alternative use of the MHC fold for immune recognition is indicated by the FcRn and FcRn/Fc co-crystal structures.

The mechanisms that regulate immunoglobulin G (IgG) catabolism are little understood. We have previously found unusually low IgG concentrations in sera of mice homozygous for a targeted disruption of the β2‐microglobulin gene. We therefore investigated whether this might result, at least in part, from increased clearance of IgG from the systemic circulation in mice lacking β2‐microglobulin. We compared the half‐lives of radiolabelled mouse IgG1 injected intravenously into β2‐microglobulin−/− mice and wild‐type or heterozygous siblings. The clearance of 125I‐labelled IgG1 was strikingly more rapid in the mice lacking β2‐microglobulin. β2‐microglobulin−/− mice lack functional molecules of the MHC class I‐related Fc receptor, FcRn. Some mutations in mouse IgG1 that increase its clearance have recently been shown to prevent binding to FcRn in the gut. To determine whether the slower degradation of immunoglobulin in mice with β2‐microglobulin correlated with the ability of the antibody to bind FcRn, we measured the clearance of chicken IgY, which does not bind this receptor. The 125I‐labelled IgY was catabolized equally rapidly in β2‐microglobulin‐deficient and wild‐type mice. We compared the half‐lives of the four subclasses of mouse IgG in β2‐microglobulin−/−, +/−, and +/+ mice to determine whether the difference we had noted for IgG1 was peculiar to this subclass. The 125I‐labelled IgG of all subclasses, with the possible exception of IgG2b, was degraded more rapidly in the β2‐microglobulin‐deficient mice than in heterozygous or wild‐type siblings. These data suggest that FcRn can protect IgG from degradation, and is therefore important in maintaining IgG levels in the circulation.