Structure, function, and evolution of mouse TL genes, nonclassical class I genes of the major histocompatibility complex.

“Classical” MHC class I (I-a) genes are extraordinarily polymorphic, but “nonclassical” MHC class I (I-b) genes are monomorphic or oligomorphic. Although diversifying (positive) Darwinian selection is thought to explain the origin and maintenance of MHC class I-a polymorphisms, genetic mechanisms underlying MHC class I-b evolution are uncertain. In one extreme model, MHC class I-b loci are derived by gene duplication from MHC class I-a alleles but rapidly drift into functional obsolescence and are eventually deleted. In this model, extant MHC class I-b genes are relatively young, tend to be dysfunctional or pseudogenic, and orthologies are restricted to close taxa. An alternative model proposed that the mouse MHC class I-b gene thymus leukemia Ag (TL) arose ∼100 million years ago, near the time of the mammalian radiation. To determine the mode of evolution of TL, we cloned TL from genomic DNA of 11 species of subfamily Murinae. Every sample we tested contained TL, suggesting this molecule has been maintained throughout murine evolution. The sequence similarity of TL orthologs ranged from 85–99% and was inversely proportional to taxonomic distance. The sequences showed high conservation throughout the entire extracellular domains with exceptional conservation in the putative Ag recognition site. Our results strengthen the hypotheses that TL has evolved a specialized function and represents an ancient MHC class I-b gene.

Section: Phylogeny Of Mhc Class I-a and I-b Genessupporting

confidence: 82%

mentioning

confidence: 73%

Hyperconservation of the Putative Antigen Recognition Site of the MHC Class I-b Molecule TL in the Subfamily Murinae: Evidence That Thymus Leukemia Antigen Is an Ancient Mammalian Gene

Davis

Cook

Rich

et al. 2002

“…It is expressed on epithelial cells in the small intestine of all strains (3,4), suggesting that this nonclassical class I molecule may play a specialized role in mucosal immunity. The TL gene products are closely related, with Ͼ95% sequence similarity and there is evidence for evolutionary selection in mice to maintain conservation in the ␣1 and ␣2 domains of these molecules (5). TL is expressed at the cell surface in association with ␤ 2 -microglobulin (␤ 2 m) and it is predicted to fold with a conformation similar to other MHC class I proteins.…”

mentioning

confidence: 99%

Peptide-Independent Folding and CD8αα Binding by the Nonclassical Class I Molecule, Thymic Leukemia Antigen

Weber¹,

Attinger

Kemball³

et al. 2002

The nonclassical class I molecule, thymic leukemia (TL), has been shown to be expressed on intestinal epithelial cells and to interact with CD8+ intraepithelial T lymphocytes. We generated recombinant soluble TL (T18d) H chains in bacteria as inclusion bodies and refolded them with β2-microglobulin in the presence or absence of a random peptide library. Using a mAb, HD168, that recognizes a conformational epitope on native TL molecules, we observed that protein folds efficiently in the absence of peptide. Circular dichroism analysis demonstrated that TL molecules have structural features similar to classical class I molecules. Moreover, thermal denaturation experiments indicated that the melting temperature for peptide-free TL is similar to values reported previously for conventional class I-peptide complexes. Our results also show that CD8αα binding is not dependent on either TL-associated peptide or TL glycosylation.

“…Because M3 has been unknown outside the murine genera Rattus and Mus, it may also have evolved from murine or murid I-a genes. A contrasting model, similar to one proposed for H2-TL (18,19), suggests that M3 arose before the mammalian radiation.…”

mentioning

confidence: 93%

Hyperconservation of theN-Formyl Peptide Binding Site ofM3: Evidence thatM3Is an Old Eutherian Molecule with Conserved Recognition of a Pathogen-Associated Molecular Pattern

Doyle

Davis

Cook

et al. 2003

The mouse MHC class I-b molecule H2-M3 has unique specificity for N-formyl peptides, derived from bacteria (and mitochondria), and is thus a pathogen-associated molecular pattern recognition receptor (PRR). To test whether M3 was selected for this PRR function, we studied M3 sequences from diverse murid species of murine genera Mus, Rattus, Apodemus, Diplothrix, Hybomys, Mastomys, and Tokudaia and of sigmodontine genera Sigmodon and Peromyscus. We found that M3 is highly conserved, and the 10 residues coordinating the N-formyl group are almost invariant. The ratio of nonsynonymous and synonymous substitution rates suggests the Ag recognition site of M3, unlike the Ag recognition site of class I-a molecules, is under strong negative (purifying) selection and has been for at least 50–65 million years. Consistent with this, M3 α1α2 domains from Rattus norvegicus and Sigmodon hispidus and from the “null” allele H2-M3b specifically bound N-formyl peptides. The pattern of nucleotide substitution in M3 suggests M3 arose rapidly from murid I-a precursors by an evolutionary leap (“saltation”), perhaps involving intense selective pressure from bacterial pathogens. Alternatively, M3 arose more slowly but prior to the radiation of eutherian (placental) mammals. Older dates for the emergence of M3, and the accepted antiquity of CD1, suggest that primordial class I MHC molecules could have evolved originally as monomorphic PRR, presenting pathogen-associated molecular patterns. Such MHC PRR molecules could have been preadaptations for the evolution of acquired immunity during the early vertebrate radiation.