A novel type of class I gene organization in vertebrates: a large family of non-MHC-linked class I genes is expressed at the RNA level in the amphibian Xenopus.

Abstract

A Xenopus class I cDNA clone, isolated from a cDNA expression library using antisera, is a member of a large family of non‐classical class I genes (class Ib) composed of at least nine subfamilies, all of which are expressed at the RNA level. The subfamilies are well conserved in their immunoglobulin‐like alpha 3 domains, but their peptide‐binding regions (PBRs) and cytoplasmic domains are very divergent. In contrast to the great allelic diversity found in the PBR of classical class I genes, the alleles of one of the Xenopus non‐classical subfamilies are extremely well conserved in all regions. Several of the invariant amino acids essential for the anchoring of peptides in the classical class I groove are not conserved in some subfamilies, but the class Ib genes are nevertheless more closely related in the PBR to classical and non‐classical genes linked to the MHC in mammals and birds than to any other described class I genes like CD1 and the neonatal rat intestinal Fc receptor. Comparison with the Xenopus MHC‐linked class Ia protein indicate that amino acids presumed to interact with beta 2‐microglobulin are identical or conservatively changed in the two major class I families. Genomic analyses of Xenopus species suggest that the classical and non‐classical families diverged from a common ancestor before the emergence of the genus Xenopus over 100 million years ago; all of the non‐classical genes appear to be linked on a chromosome distinct from the one harboring the MHC. We hypothesize that this class Ib gene family is under very different selection pressures from the classical MHC genes, and that each subfamily may have evolved for a particular function.

Involvement of nonclassical MHC class Ib molecules in heat shock protein‐mediated anti‐tumor responses

“…Since the motif in the a3 domain that interacts with b2m is conserved in all known XNC genes [25], our first strategy was to down-regulate expression of b2m by RNA interference. We generated stable 15/0 sub-lines expressing a short hairpin RNA (shRNA) specifically targeting and silencing b2m.…”

“…Phylogenetic analysis of class Ib genes indicates that they have rapidly diversified during evolution and display many species-specific specializations, which complicates the study of their functions [22]. Nevertheless, the identification of class Ib genes in all taxa of jawed vertebrates [23][24][25] suggests that some of them should have significant biological relevance and possibly conserved function.…”

“…In Xenopus there are roughly 20 class Ib genes [25]; these are distant from the MHC locus but located at the telomeric extremity of the same chromosome [26]. Xenopus nonclassical MHC class Ib (XNC) genes, like their mammalian counterparts, are heterogeneous, have a low polymorphism (especially in the peptide-binding domain) and have more restricted tissue distribution than class Ia molecules.…”

The evolutionary ecology of the major histocompatibility complex

“…An increasing number of MHC genes from non-model species are being characterised for comparison (Shiina et al, 2002;Kelley et al, 2005), and are highlighting considerably more variation in architecture. Large differences in the number of MHC loci are apparent across species, and some groups have silenced particular loci or have them arranged in unlinked gene clusters (Flajnik et al, 1993;Hansen et al, 1999;Kuroda et al, 2002). What is clear is that despite the conserved proximate function of MHC in immune recognition, the architecture of MHC genes varies sufficiently that a small number of model species is insufficient to describe the complex processes of antigen binding and recognition.…”

Nonclassical MHC class I-dependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians

“…The Xenopus nonclassical gene (XNC) class Ib gene XNC10 is one of X. laevis 30 XNC genes (14)(15)(16). XNC10 represents a unique class Ib monogenic lineage phylogenetically distinct from both X. laevis class Ia and other XNC genes but highly conserved among divergent Xenopus species and characterized by interspecies sequence conservation in its putative antigen binding domain (15).…”