Cd1, Tuberculosis, and the Evolution of Major Histocompatibility Complex Molecules

Although the role of class I and class II MHC in adaptive immunity against microbial pathogens is clear, the participation of nonpolymorphic MHC molecules in host defense remains less well defined. Roles for murine class I MHC molecule Qa-2 and class Ib molecule H2-M3 have been suggested (1–3), and accumulating data have prompted speculation that CD1 family members may be important in immunity against pathogenic mycobacteria and parasites (4). In this issue, Spada et al. report the restriction of at least some human V g 2/V d 1 T cells, the most common tissue g / d T cells, by CD1c (5). Like other populations of CD1restricted T cells, as discussed further below, the CD1crestricted cells were autoreactive in vitro. These cells produced IFNg , but not IL-4, and displayed cytotoxicity against CD1c 1 targets, leading the authors to speculate that such cells might be involved in innate host defense against prevalent pathogens. In this way, g / d and other CD1restricted T cells would represent unique small populations of lymphocytes that have been evolutionarily maintained because of their capacity to react rapidly to microbes. However, pathogens are clever, and an equally plausible hypothesis is that pathogens have exploited unusual T cell populations that exist for reasons different than immunity. Indeed, based on comparisons with other nonpolymorphic MHC molecules, we suspect that the primary role of such molecules may not entail immunity to infectious organisms, but may rather underlie a basic mechanism for the maintenance of cell and tissue homeostasis. The ancient process by which MHC molecules sample distinct cellular compartments may have been later coopted by classical MHC molecules to mediate protective immunity at the time of acquisition of bacteria-derived recombination activating gene (RAG) transposases and the establishment of a system for adaptive immunity (6). By this alternate hypothesis, mycobacteria uniquely exploit the underlying biological processes mediated by CD1. The CD1 Family: Genomic Organization and Structure The CD1 family comprises a heterogeneous group of b 2-microglobulin ( b 2m)-associated transmembrane proteins that bear a strong structural resemblance to the classic MHC antigens (4). However, in contrast to the latter, CD1 genes are relatively nonpolymorphic, and are encoded by genes distant from the classic MHC loci. In humans, five CD1 genes on chromosome 1 are known to encode four proteins, designated CD1a, b, c, and d; CD1e may represent a pseudogene. The CD1 family is further subdivided into group 1, comprising CD1a, b, and c, and group 2, comprising CD1d, based on sequence and functional homology. In the mouse, an ancient translocation likely resulted in the loss of the group 1 genes (7); only CD1d1 and a duplicated gene, CD1d2, remain on the syntenic region of chromosome 3. Crystallographic analysis of mouse CD1d1 confirmed the preservation of domain organization between this molecule and the structure of classic MHC (8). As with class I MHC, an externally disposed binding cleft formed by an eightstranded antiparallel b -sheet floor bounded by the a 1 and a 2 helices provided evidence for a molecule involved in ligand display. However, in contrast to the sequential small binding pockets that accommodate individual amino acids of the peptide backbone in classic MHC, the CD1d1 cleft consisted of two large pockets lined with hydrophobic residues. Although capable of binding long, highly hydrophobic peptides (9), it is likely that the unique structure underlies the capacity of CD1 to present lipid ligands. The functionally interchangeable nature of mouse and human CD1d molecules, such that mouse CD1 can present to human CD1-restricted T cells and vice versa (10), suggests that the human CD1d structure will be similar.