CD1 displays its own negative regulators

Abstract

After two decades of the study of lipid antigens that activate CD1-restricted T cells, new studies show how autoreactive αβ T-cell receptors (TCRs) can directly recognize the outer surface of CD1 proteins in ways that are lipid-agnostic. Most recently, this lipid agnosticism has turned to negativity, with the discovery of natural CD1 ligands that dominantly negatively block autoreactive αβ TCR binding to CD1a and CD1d. This review highlights the basic differences between positive and negative regulation of cellular systems. We outline strategies to discover lipid inhibitors of CD1-reactive T cells, whose roles in vivo are becoming clear, especially in CD1-mediated skin disease.

Figure 1.

Differing modes of TCR contact with CD1 establish the older corecognition and newly proposed direct recognition models.

Figure. 2

Sphingomyelins with short alkyl chains allow the choline headgroup to reside inside CD1a, but longer chain lipids shift the ligand so that the choline headgroup extends ~6 angstroms above the CD1 roof. Long chain sphingomyelins with blocking properties are selectively captured by CD1a in human cells.