From an evolutionary perspective it is interesting that some class Ib genes seem to have evolved early, before the divergence of the cartilaginous fishes from the vertebrate line, and are likely to have homologs in all vertebrates. Other class I genes have independently evolved into classical and nonclassical loci within the vertebrate lineages that have been studied (for example, cartilaginous fishes, lobe-finned fishes, ray-finned fishes, amphibians, and mammals). Sequence data have also revealed homologs of the mammalian MHC-I and MHC-II gene families in virtually all jawed vertebrates including sharks, bony fishes, reptiles, and birds. In contrast, CD1 genes may not be as old as
Chapter 6: Antigen Presentation to T Lymphocytes
Fig. 6.28 Structure of CD1 binding to a lipid antigen. Shown are top and side views of the structure of mouse CD1d bound to C8PhF, a synthetic lipid that is an analog of α-GalCer. The helical side chains of CD1d (blue) form a binding pocket that is generally similar in shape to the binding pockets of MHC class I and II molecules. However, the C8PhF (red) ligand binds to CD1 molecules in a distinctly different conformation from that of peptides. The two long alkyl side chains extend deep inside the binding groove (see side view), where they make contacts with hydrophobic residues. This orientation of the alkyl side chains places the carbohydrate component of α-GalCer to the outer surface of CD1, where it can be recognized by the T-cell receptor. In addition, the CD1 molecule contains an endogenous lipid molecule (yellow) derived from cellular sources that binds to a distinct region within the groove and prevents a large pocket adjacent to the α-GalCer-binding region from collapsing. The ability to incorporate additional ligands into the binding groove may provide flexibility to CD1d in accommodating a variety of exogenous glycosphingolipids from microorganisms. Courtesy of I.A. Wilson.
other MHC class Ib genes. They have been found only in a subset of these animal groups and appear to be missing in fish. This pattern of CD1 occurrence in the genomes of living species suggests the emergence of CD1 in an early terrestrial vertebrate.
6-19 The nonclassical MHC class I molecule MR1 presents microbial folate metabolites to MAIT cells.
Another nonclassical MHC class Ib molecule is MR1 (MHC-related protein 1). MR1 associates with β2-microglobulin and is encoded outside the MHC, but its function was originally known only in relation to a conserved population of α:β T cells known as mucosal associated invariant T cells (MAIT cells). In Section 4-18, we introduced MAIT cells as one population of T cells expressing the CD8α homodimer, but they are uniquely characterized by expressing an invariant α chain of the T-cell receptor, specifically human Vα7.2J2–Jα33 (or in mouse, Vα19) . This α chain pairs with a limited number of Vβ chains, typically Vβ2 or Vβ13. MAIT cells are very abundant in humans and can comprise up to 10% of the lymphocytes in the peripheral blood and tissues such as the liver. They are also present in mesenteric lymph nodes and the mucosa of the intestine. Studies of MAIT cells revealed that their development requires the expression of MR1, and further, that a wide spectrum of microbes, including diverse bacteria and yeast, can activate MAIT cells. However, when they were originally identified around a decade ago, it was unclear what, if any, ligand is being recognized by these cells.