αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands

Abstract

A central paradigm in αβ T cell-mediated immunity is the simultaneous co-recognition of antigens and antigen-presenting molecules by the αβ T cell antigen receptor (TCR). CD1a presents a broad repertoire of lipid-based antigens. We found that a prototypical autoreactive TCR bound CD1a when it was presenting a series of permissive endogenous ligands, while other lipid ligands were nonpermissive to TCR binding. The structures of two TCR-CD1a-lipid complexes showed that the TCR docked over the A' roof of CD1a in a manner that precluded direct contact with permissive ligands. Nonpermissive ligands indirectly inhibited TCR binding by disrupting the TCR-CD1a contact zone. The exclusive recognition of CD1a by the TCR represents a previously unknown mechanism whereby αβ T cells indirectly sense self antigens that are bound to an antigen-presenting molecule.

Human autoreactive T cells recognize CD1b and phospholipids

“…4B). Therefore, similar to models recently proposed for CD1a (20,21), cellular autoreactivity is plausibly controlled by the ratio of activating to blocking ligands on the surface, rather than the failure to recognize self-lipids and the introduction of foreign lipids during infection. Overall, PG is much more abundant in bacteria than in mammalian cells.…”

“…Next we sought to understand why T cells isolated using lipids from three differing bacterial species could also recognize CD1b proteins expressed on cells that were not exposed to bacterial lipids. This might be explained if TCRs directly bind CD1b without regard to the loaded lipid, similar to a recently identified mechanism by which a CD1a-autoreactive TCR binds an unliganded facet of the CD1a surface (21). However, lipid-independent recognition was unlikely, as bacterial lipids strongly augmented dextramer staining of all four T-cell lines (Fig.…”

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

“…By definition, antigenic lipids ligate TCRs to antigen-presenting molecules with higher affinity than nonantigenic lipids, so we reasoned that a recombinant iNKT TCR with relatively high affinity for CD1d-α-galactosylceramide complexes, known as 2C12 (16), might selectively trap those CD1d complexes carrying milk-derived antigens, while leaving behind CD1d molecules that were bound to nonantigenic lipids. Such a TCR trap approach was recently used to identify CD1a autoantigens (17). We hypothesized that this approach might be feasible for CD1d and milk-derived antigens, because partially enriched milk fractions could mediate the physical binding of CD1d tetramers to cells expressing an iNKT cell Vα14Jα18 Vβ8.2Jβ2.1 TCR, but not to cells expressing a sulfatide-reactive diverse NKT cell Vα1Jα26 Vβ16Jβ2.1 TCR (18,19).…”

“…This approach uses ternary complex formation both as the preparative method to recover lipids of interest and as the assay demonstrating the lipid's role in ligating CD1d and TCR. The TCR trap assay has also been used successfully to identify CD1a ligands (17), and could be used to identify ligands for other CD1 isoforms, or even MR1. This approach will allow tracking of rare lipids from virtually any source, including from complex mixtures, or limited starting materials, which represent common challenges when starting with mammalian tissues and cells.…”

Donor-unrestricted T cells in the human CD1 system

“…Thus, unlike the sides of the clefts that form from rigid secondary structural elements (the α1- and α2-helices), the A′ roof is a tenuous structure with a regulatory function. Highlighting the weak structural nature of the A′ roof, binary crystal structures of CD1a-sphingomyelin complexes show that sphingomyelin can penetrate the A′ roof by disrupting a triad of residues that form interdomain interactions (Birkinshaw et al 2015). The A′ roof is present in CD1a, CD1b, CD1c, and CD1d, and it has no equivalent in MHC I or MHC II structures.…”