Antigen-presenting function of the TL antigen and mouse CD1 molecules.

Abstract

The hallmark of all the nonclassical antigen-presenting molecules, including nonclassical class I and nonclassical class II (Karlsson et al. 1992) molecules, is their lack of polymorphism. It is presumed, therefore, that these nonclassical molecules must have a distinct antigen-presenting function in which polymorphism is not advantageous. In some cases this may involve presentation of a nonpeptide antigen, as has been demonstrated for human CD1b. It is possible that a molecule adapted to present bacterial lipids would remain relatively nonpolymorphic, because a lipid, which is the end product of a complex biosynthetic pathway, is likely to evolve less rapidly than a short stretch of amino acid sequence containing a T-cell epitope. Alternatively, the lack of polymorphism could reflect the presentation by these molecules of relatively invariant peptides, such as those derived from heat shock proteins. It also is possible that a nonpolymorphic molecule could be selected for the presentation of modified peptides. An example of this is the M3 molecule, which can bind even short peptides as long as they have a formylated N-terminus (Fischer Lindahl et al. 1991). Based upon their structural differences, we believe it is likely that the TL antigen and mCD1 are likely to present different types of ligands. The presence in the TL antigen of the conserved amino acids, which in class I normally from hydrogen bonds with peptides, suggests that the TL antigen also can present nanomeric peptides. A peptide antigen-presenting function also is suggested by the expression of the TL antigen by at least one antigen-presenting cell type, the epithelial cell of the intestine, and by the ability of alloreactive T cells to recognize the TL molecule. While we favor the hypothesis that the TL antigen presents peptides, the data cited above do not constitute formal proof of any kind of antigen-presenting function, and it remains possible that the TL antigen does something else. As noted above, no attempts to elucidate the structure of the ligands bound to the TL antigen have so far succeeded, including the screening of bacteriophage display libraries (Castaño, A.R., Miller, J.E., Holcombe, H.R., unpublished data). In contrast, our recent work has demonstrated that mCD1 presents relatively long peptides with a structured motif distinct from classical class I molecules. This mCD1-binding motif, which is present in a wide range of proteins, does not by itself provide a simple explanation for the lack of mCD1 polymorphism and, as noted above, it remains possible that the natural ligand for mCD1 is a nonpeptide structure. Besides their lack of polymorphism, the TL antigen and mCD1 molecules share two additional features in common which might give insight into their their biological role. First, their surface expression does not depend upon the presence of a functional TAP transporter, and they probably can reach the cell surface as empty molecules. Second, both molecules are expressed by epithelial cells in the intestine. This leads to the speculation that these two nonclassical class I molecules could be involved in sampling or uptake of lumenal peptides for their ultimate presentation to cells of the systematic immune system. For example, longer lumenal peptides could be taken up by mCD1, and perhaps by the TL antigen, and then further processed to nonamers for presentation by classical class I molecules. They also could be transported across the epithelial cell by the TL antigen or mCD1 and subsequently presented by either class I or class II molecules expressed by cells in the lamina propria. This sampling or uptake mediated by either the TL antigen or mCD1 could play a role in the induction of immune responses, or more likely perhaps, in the induction of systemic oral tolerance to peptide antigens.(ABSTRACT TRUNCATED)