A Novel Instance of Class I Modification (cim) Affecting Two of Three Rat Class I RT1-A Molecules Within One MHC Haplotype

Abstract

T he number of genes for MHC class I molecules varies greatly between species: from ϳ11 in pigs (1) to several thousand in the African pigmy mouse (2). Among the complement of class I genes in a species, some are designated classical class I, or MHC class Ia, genes. The protein products of the class Ia genes share certain characteristics. These include high cell surface expression levels relative to the levels of MHC class Ib genes, a major role in repertoire formation and Ag presentation for substantial numbers of ␣/␤ CD8 ϩ T lymphocytes, the ability to provoke strong cellular CD8 ϩ T cell responses in the context of allotransplantation, and a tendency toward a high degree of genetic polymorphism. MHC class I genes are found at several different positions within each MHC complex. A unifying description of mammalian MHC class I gene organization has been provided by Amadou (3), who pointed out that clusters of class I genes, varying in size from one species to another, are located at certain positions within a linear framework of conventional genes that maintains an evolutionarily conserved order.The most detailed investigations of MHC class I genetics have involved studies of this system in humans and laboratory mice. Comparative studies in other species, however, have served to stress the remarkable plasticity of this system. The description of the MHC of the laboratory rat (Rattus norvegicus) is now well advanced (4). Close scrutiny of MHC class Ia gene expression in the rat has uncovered surprising differences from its fellow murine, the mouse. 1) Rat MHC class Ia genes are all located to one side (centromeric) of the MHC class II region, i.e., there is no evidence for an H2-D or -L equivalent in the rat (the rat class Ia region is called RT1-A).2) The number of MHC class Ia genes per MHC haplotype is a variable (5, 6). Similar observations have been reported for cattle (7). 3) The TAP peptide transporter, which supplies peptides for MHC class I assembly, is functionally dimorphic in the rat (8 -10). The rat MHC class Ia system has evolved alleles that apparently take advantage of the broader peptide specificity of the rat TAP-A transporter allele, while the mouse class Ia alleles reflect a more restrictive TAP, which has properties similar to those of rat TAP-B (6, 11).The polymorphism of rat TAP described above was discovered on account of a phenomenon termed class I modification (cim).4 A rat MHC class Ia allele named RT1-A a showed striking differences in expression and antigenicity for T lymphocytes depending on the genetic origin of the MHC class II region with which it was expressed (8,12,13). It emerged that allelism of the MHC class II-linked TAP2 gene was responsible for the observations. TAP heterodimers containing the TAP2A allele could readily supply the type of peptides required for RT1-A a to assemble, but those

Natural Polymorphisms in Tap2 Influence Negative Selection and CD4∶CD8 Lineage Commitment in the Rat

“…The number of RT1-A genes in standard inbred rat strains varies from one in the RT1 lv1 and RT1 a haplotypes to three in the RT1 n,o,d,m haplotypes [14], [18]. It has therefore been suggested that the number of RT1-A genes influences the selection of CD8 T cells [36].…”

“…It has therefore been suggested that the number of RT1-A genes influences the selection of CD8 T cells [36]. The expression of RT1-A at the protein level has previously been characterized using allotypic antibodies [18], [49]–[52], while the phenotypes we mapped in the HS and RCS were determined using the widely reactive MHC class I antibody OX18, which does not discriminate between different isoforms of RT1-A. In order to assess the number of functional protein-coding RT1-A genes in DA.1IR85 and to confirm the expression of RT1-A a , A1 h and A2 h , and A u as the only class Ia molecules in DA and the Tcs1 -congenic strains, we analyzed trypsin-digested cell lysates of IFN-γ stimulated splenocytes from these strains by mass spectrometry.…”

“…MHC class Ib molecules are structurally similar to class Ia molecules but the corresponding class Ib genes are less polymorphic, expressed at lower levels and several are pseudogenes [16], [17]. The number of functional class Ia genes ( RT1-A1, RT1-A2, RT1-A3 ) in the rat varies between one and three in standard inbred strains [18], [19]. These genes are highly polymorphic and densely expressed on the surface of virtually all nucleated cells where they engage in presentation of intracellular antigens to cytotoxic CD8 T cells.…”

Identification of an MHC Class I Ligand for the Single Member of a Killer Cell Lectin-like Receptor Family, KLRH1

“…Thus, of the 24 haplotypes tested, and all the different class I molecules that make up these haplotypes, KLRH1 recognition appears to be limited to only one molecule, the classical class I molecule RT1-A2 n . Although different rat haplotypes express different numbers of MHC class I genes and may lack one or more RT1-A genes, several of the haplotypes tested are known to express an RT1-A2 or A2-like class I molecule (26). It can hence be concluded that the KLRH1 receptor is specific for the A2 allelic variant expressed in the n haplotype.…”

The Role of Natural Killer Cells in the Defense against <i>Listeria</i><i>monocytogenes</i> Lessons from a Rat Model

“…The classical RT1-A region contains one, two or three MHC-I genes depending on the haplotype. For instance, the RT1 k and RT1 u haplotypes contain one, RT1 c two and RT1 n three expressed MHC-Ia genes [62][63][64][65] . Rat NK cell receptors may show exquisite specificity for certain class I alleles.…”