Immunology and Cell Biology (2004) 82, 285–294 doi:10.1111/j.1440-1711.2004.01257.x © 2004 Australasian Society for Immunology Inc. Special Feature Antigen specificity of semi-invariant CD1d-restricted T cell receptors: The best of both worlds? JENNY E GUMPERZ, PhD Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706, USA Summary T lymphocytes are characterized by the use of structurally diverse TCR. The discovery of subsets of canonical T cells that have structurally homogeneous TCR presents an enigma: What antigens do these T cells recognize, and how does their antigen specificity relate to their functions? One subset of canonical T cells is restricted by CD1d, a non-classical antigen presenting molecule that presents lipids and glycolipids. Canonical CD1d-restricted T cells have semi-invariant TCR consisting of an invariantly rearranged TCR α chain, paired with diversely rearranged TCRβ chains. Most respond strongly to the unusual glycolipid α-galactosylceramide (α-GalCer), and can also respond to cellular antigens presented by CD1d. Mounting evidence indicates that α-GalCer responsive T cells are heterogeneous in their reactivities to cellular antigens, suggesting that an individual semi-invariant TCR may be capable of recognizing more than one ligand. Recent crystal structures of CD1b molecules with three different bound lipids indicate that the antigenic features of lipids may be localized over a smaller area than those of peptides, and that the positioning of the polar head group can vary substantially. A model that explains how CD1d-restricted T cells could possess both conserved and heterogeneous antigen specificities, is that different lipid antigens may interact with distinct areas of a TCR due to differences in the positioning of the polar head group. Hence, canonical CD1d-restricted TCR could recognize conserved antigens via the invariant TCR α chain, and have diverse antigen specificities that are conferred by their individual TCRβ chains. T cell receptor structure Like antibody molecules, TCR form through an unusual process of genetic recombination that produces extraordinary sequence heterogeneity at specific sites within the protein. 1–5 TCR consist of two polypeptide chains, either α and β, or γ and δ. Each chain is formed by somatic rearrangement of germ line DNA sequences, which brings together a series of gene segments called variable (V ), joining (J ), and con- stant (C ), and an additional segment call diversity (D) for the β and δ chains. Structural variation among TCR is due to different pairings among α and β or γ and δ chains, the usage of different combinations of V, J, and D gene segments in each chain, and to a process called N-region diversification that introduces random changes in nucleotide sequence and DNA length at the junctions between the segments. T cell receptor sequence variability is mainly focused into three specific areas of each chain called complementarity determining regions (CDR), which correspond to surface exposed loops that come together to form one face of the TCR. 6–10 This face of the TCR recognizes antigens – usually peptides – that are bound and presented at the cell surface by antigen presenting molecules. The first and second CDR loops of each chain (CDR1 and CDR2) are encoded solely by the V genes, while the third CDR loop (CDR3) includes the V(D)J junctional region, and these loops are therefore the most variable regions of the TCR. 11,12 X-ray crystallographic and mutagenesis studies have shown that when TCR dock onto antigen presenting molecules, the CDR3 loops are posi- tioned centrally over the antigen binding groove and make specific contacts with accessible portions of bound peptide antigens. 13–16 Thus, the most highly heterogeneous TCR regions are focused on antigen recognition. This translates into highly specific detection properties, with each TCR capable of recognizing only a very limited number of peptides. The value of diversity Although any one T cell can only respond to very specific antigenic stimuli, there is a tremendous variety of different TCR structures within the T-cell population as a whole. 2 The diversity in the TCR repertoire permits recognition of an almost unlimited number of antigens, and is what makes the adaptive immune system effective at dealing with the ‘unknown’ – responding to novel pathogens and rapidly tracking pathogen mutations. Thus, the expression of highly heterogeneous TCR within the T cell population is a critical component of its effectiveness. The enigma of canonical T cell receptors Contrasting with this paradigm is the discovery of T-cell subpopulations that express canonical TCR, or TCR in which one or both chains are completely or nearly structurally invariant. 17–24 Some subsets of canonical T cells are not simply the result of the proliferation of a single T-cell clone, as clear evidence can be found that individual subclones developed independently, such as the presence of one diversely Correspondence: Jenny E Gumperz, PhD. Email: jegumperz@wisc.edu Received 8 March 2004; accepted 8 March 2004.