Structural Basis for Lipid-Antigen Recognition in Avian Immunity

Abstract

CD1 proteins present self and foreign lipid antigens to activate specific T cells in the mammalian immune system. These T cells play an important role in controlling autoimmune diseases, suppression of tumor growth and host defense against invading pathogens. Humans utilize five CD1 isoforms, while only two exist in birds. Unlike mammals CD1, the structure of chicken CD1-2, showed a primitive lipid-binding groove, suggesting that chicken may only recognize single chain lipids. In contrast, the crystal structure of the second chicken CD1 isoform, chCD1-1, reported here at 2.2 Å resolution, reveals an elaborated binding groove with a dual-pocket dual-cleft architecture. The A′ and F′ deep pockets are separated from each other, but each is connected to a hydrophobic surface cleft, which may participate in lipids binding. The long endogenous ligand found inside the binding groove of chCD1-1, together with binding data on various glycolipids and mycolic acid, strongly suggest that the unique avian CD1 family could bind long dual- and possibly tri-acyl chain lipids.

The CD1 family: serving lipid antigens to T cells since the Mesozoic era

“…Since MHC molecules are found even earlier in evolution (>450 mya), as early as in cartilaginous fish (e.g., shark), it is tempting to speculate that a primordial CD1 can be found that is derived from an evolutionary early MHC gene. The crystal structures of both chicken CD1-1 (chCD1-1) and chCD1-2 had been determined to address this question (Dvir et al 2010; Zajonc et al 2008b). …”

“…Since the structure of chCD1-2 revealed a primitive binding pocket, the structure of chCD1-1 had been determined in an attempt to structurally characterize all CD1 proteins of a single species (Dvir et al 2010). The structure of chCD1-1 identified an unexpectedly complex lipid-binding groove.…”

“…The structure of chCD1-1 identified an unexpectedly complex lipid-binding groove. The size of the binding groove is that of between human CD1a and CD1d (1440 Å 3 volume) (Dvir et al 2010). It consists of a rather large A′ pocket and a more restricted and narrow F′ pocket (Fig.…”

“…Interestingly, both A′ and F′ pockets open into a hydrophobic cleft at the protein surface, which also participate in antigen binding. This lipid presentation is on top of the binding pocket, effectively increasing the size of lipids that can be presented by chCD1-1 (Dvir et al 2010). The crystal structure also revealed the presence of endogenous ligands in both the A′ and F′ pockets.…”

Location, location, location: the evolutionary history of CD1 genes and the NKR-P1/ligand systems

“…Such hydrophobic regions are consistent with binding lipids as do eutherian CD1 molecules, and this was tested explicitly by X-ray structures for the extracellular regions of chicken CD1.1 and CD1.2 expressed in insect cells (Zajonc et al 2008; Dvir et al 2010). These structures show that both molecules have the same general structure as human CD1 molecules but differ in the details of the binding site.…”