Evan M. Beckman

Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells

Abstract Human Vγ2Vδ2 + T cells recognize mycobacterial non-peptide antigens, such as isopentenyl pyrophosphate, and their synthetic analogs, such as monoethyl phosphate, through a TCR-dependent process. Here, we examine the presentation of these antigens. Vγ2Vδ2 + T cells recognized secreted prenyl pyrophosphate antigens in the absence of other accessory cells but, under such conditions, required T cell-T cell contact. Recognition required neither the expression of classical MHC class I, MHC class II, or CD1a, CD1b, and CD1c molecules, nor MHC class I or class II peptide loading pathways. Fixed accessory cells also presented the prenyl pyrophosphate antigens to γδ T cells. Thus, in contrast with the presentation of conventional peptide antigens, protein antigens, and superantigens to αβ T cells, prenyl pyrophosphate antigens are presented to γδ T cells through a novel extracellular pathway that does not require antigen uptake, antigen processing, or MHC class I or class II expression. This pathway allows for the rapid recognition of bacteria by γδ T cells and suggests that γδ T cells play a role in the early response to bacterial infection.

Fine specificity of TCR complementarity-determining region residues and lipid antigen hydrophilic moieties in the recognition of a CD1-lipid complex.

αβ TCR can recognize peptides presented by MHC molecules or lipids and glycolipids presented by CD1 proteins. Whereas the structural basis for peptide/MHC recognition is now clearly understood, it is not known how the TCR can interact with such disparate molecules as lipids. Recently, we demonstrated that the αβ TCR confers specificity for both the lipid Ag and CD1 isoform restriction, indicating that the TCR is likely to recognize a lipid/CD1 complex. We hypothesized that lipids may bind to CD1 via their hydrophobic alkyl and acyl chains, exposing the hydrophilic sugar, phosphate, and other polar functions for interaction with the TCR complementarity-determining regions (CDRs). To test this model, we mutated the residues in the CDR3 region of the DN1 TCR β-chain that were predicted to project between the CD1b α helixes in a model of the TCR/CD1 complex. In addition, we tested the requirement for the negatively charged and polar functions of mycolic acid for Ag recognition. Our findings indicate that the CDR loops of the TCR form the Ag recognition domain of CD1-restricted TCRs and suggest that the hydrophilic domains of a lipid Ag can form a combinatorial epitope recognized by the TCR.

MHC class I-like, class II-like and CD1 molecules: distinct roles in immunity

Genes encoding MHC class I-like, class II-like and CD1 molecules have evolved to assume specific immunological functions. Some class I-like molecules, including H-2M3 and Qa-2, present formylated bacterial peptides or have distinct peptide-binding motifs. The class II-like DMA and DMB gene products play a role in presentation of peptide antigen by class II molecules. By contrast, CD1 molecules appear to have evolved separately into presenters of nonprotein antigens and into TCR ligands with specialized roles in the immune response. Thus, class I-like, class II-like and CD1 molecules appear either to serve important independent functions or to complement MHC class I and class II. It is expected that future efforts will increasingly reveal the functional ramifications of these molecules.

Antigen presentation by CD1 and MHC-encoded class I-like molecules

Three known lineages of antigen-presenting molecules restrict T-cell responses to microbial antigens: MHC class I and MHC encoded class I like molecules present peptides derived from the proteolysis of intracellular pathogens, MHC class ii molecules present peptides derived from the proteolysis of extracellular pathogens and CD1 molecules present unique microbial lipids and glycolipids. Recent studies have indicated that CD1 molecules mediate a novel system of antigen presentation and that MHC-encoded class I-like molecules can present unique subsets of intracellularly derived peptides.