A molecular basis of human T cell receptor autoreactivity toward self-phospholipids

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Science Immunology  20 Oct 2017:
Vol. 2, Issue 16, eaao1384
DOI: 10.1126/sciimmunol.aao1384

Avoiding lipid autoreactivity

The importance of self-tolerance is appreciated in the context of presentation of peptide antigens to T cells. Much less is known about how lipid-reactive T cells avoid reacting to abundant self-lipids. Here, Shahine et al. studied an autoreactive T cell receptor (TCR) that recognizes a rare self-phospholipid, phosphatidylglycerol (PG). They solved the structure of this TCR bound to CD1b-PG complex and compared this with previously solved structures of CD1-lipid-TCR ternary complexes. The authors found that, in the context of CD1b, TCR binding to abundant self-phospholipids is usually sterically or electrostatically repelled, and propose that this facilitates avoidance of T cell autoreactivity to ubiquitous self-phospholipids.


Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, including psoriasis, contact hypersensitivities, and allergies. However, the molecular mechanisms for regulating T cell autoreactivity toward lipid antigens remain unclear. We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids. The spectrum of self-antigens captured by CD1b skews toward abundant membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine. However, TCRs can specifically recognize rare phospholipids, including phosphatidylglycerol (PG). The structure of an autoreactive TCR bound to CD1b-PG shows that discrimination occurs through a marked induced fit movement of PG so that its polar head group fits snugly into the cationic cup of the TCR. Conversely, TCR binding toward ubiquitous self-phospholipids was sterically or electrostatically repelled. Accordingly, we describe a mechanism of TCR autoreactivity toward rare phospholipids and avoidance of autoreactivity to the most abundant self-phospholipids.

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