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

Adam Shahine,Jamie Rossjohn,D. Branch Moody,Ildiko Van Rhijn,Sarah Iwany,Stephanie Gras,Tan-Yun Cheng

doi:10.1126/sciimmunol.aao1384

Abstract

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.

Highlights

T cells, via their T cell antigen receptors (TCRs), play a crucial role in protective immunity by recognizing foreign peptide antigens when presented by molecules encoded by the major histocompatibility complex (MHC) [1]
Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, including psoriasis, contact hypersensitivities, and allergies
We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids

Summary

Introduction

T cells, via their T cell antigen receptors (TCRs), play a crucial role in protective immunity by recognizing foreign peptide antigens when presented by molecules encoded by the major histocompatibility complex (MHC) [1]. We have a broad understanding of the molecular mechanisms limiting the MHC-mediated response to self-peptides [3], the basis of avoidance of self-reactivity toward lipidic autoantigens presented by the CD1 family is less clear. The human CD1 family of antigen-presenting molecules (CD1a, CD1b, CD1c, and CD1d) is structurally related to MHC class I (MHC-I). Each of the four types of human CD1 antigen-presenting molecules has a distinctly shaped antigen-binding cleft, differing subcellular routes of trafficking, and distinct modes of transcriptional regulation [4], suggesting that CD1 family members have distinct functions [6]. Most studies on CD1 have focused on CD1d-restricted natural killer T (NKT)

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