Lipids hide or step aside for CD1-autoreactive T cell receptors

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Highlights

  • Human CD1-autoreactive T cells are common and can mediate autoimmunity.

  • T cell receptors can bind directly to CD1 without contacting bound lipid.

  • Lipids can hide buried within the CD1 cleft.

  • Lipids can emerge toward the edge of CD1 and side step T cell receptors.

  • CD1 autoreactivity is seen among αβ+, Vδ1+ and δ/αβ+ T cells.

Peptide and lipid antigens are presented to T cells when bound to MHC or CD1 proteins, respectively. The general paradigm of T cell antigen recognition is that T cell receptors (TCRs) co-recognize an epitope comprised of the antigen and antigen presenting molecule. Here we review the latest studies in which T cells operate outside the co-recognition paradigm: TCRs can broadly contact CD1 itself, but not the carried lipid. The essential structural feature in these new mechanisms is a large ‘antigen free’ zone on the outer surface of certain antigen presenting molecules. Whereas peptides dominate the exposed surface of MHC-peptide complexes, all human CD1 proteins have a closed, antigen-free surface, which is known as the A′ roof. These new structural models help to interpret recent biological studies of CD1 autoreactive T cells in vivo, which have now been broadly observed in studies on TCR-transgenic mice, healthy humans and patients with autoimmune disease.

Section snippets

Co-recognition

T cell activation occurs after T cell receptor (TCR) co-recognition of peptide-MHC complexes. The term ‘co-recognition’ emphasizes that TCRs are highly specific for the peptide antigen and the MHC encoded antigen presenting molecule. TCRs are restricted to a particular MHC allomorph. The failure if a TCR to distinguish similar peptides can emerge as molecular mimicry, which drives autoimmunity [1]. The discovery of CD1 presentation of lipid antigens to αβ and γδ T cells [2••] was followed by

Absence of interference

Early evidence showing that mouse and human CD1 isoforms activate some T cells without the addition of defined exogenous ligands hinted at a proclivity for autoreactivity in the CD1 system [2••]. For MHC-reactive T cells, autoreactivity usually derives from specific TCR recognition of a defined peptide. Prior to experimental dissection of the molecular basis CD1 autoreactivity, several theoretical mechanisms were highlighted in an early review, including the direct recognition of CD1 itself [6

Buried ligand model

All human CD1 proteins have A′ and F′ pockets, which were named after the A to F pockets in MHC I (Figure 2). Conventionally, CD1 proteins appear with the A′ pocket on the left and F′ pocket on the right. The surface above the A′ pocket is closed, forming the A′ roof. A portal over the F′ pocket allows antigens to protrude to the surface (Figure 1). For the 3C8 TCR bound to CD1c [20••] the TCR-α chain sits on the A′ roof and the TCRβ chain spans across the F′ portal to contact its right margin.

Left–right mismatch

The left–right mismatch model was established from the structure of the BK6 TCR bound to CD1a-lysophosphosphatidylcholine (LPC) [18]. The lipid ligand is not fully buried within CD1a. Instead, the phosphocholine head group exits through the F′ portal to rest on the far right margin of the CD1a surface. The TCR takes a left-sided footprint, leaving an option for emergence of some hydrophilic head group moieties through the F′ portal without TCR-lipid contact (Figure 1). Because the TCR in the

γδ T cell response to CD1

Increasing evidence demonstrates Vδ1+ γδ T cell recognition of CD1d [21] and CD1c [2••, 22, 23]. Ternary crystal structures show that the TCR known as DP10.7 binds CD1d-sulfatide [24] and that the 9C2 TCR binds CD1d-α-galactosylceramide [25]. Similarly, a hybrid δ/αβ TCR known as 9B4 binds CD1d-α-galactosylceramide [26]. In all three cases, the TCRs do not broadly surround the protruding head groups, as seen for NKT TCRs and other head group specific mechanisms [4]. Instead these three TCRs

CD1 proteins provide a ligand free surface

For MHC-peptide, co-recognition is universal. More than a hundred solved ternary structures involving MHC I and II [1] show the now familiar face of antigen complexes. The peptide runs mostly or all the way across the lateral dimension of the MHC platform, where it comprises 20 percent or more of the exposed surface area (Figure 2). Despite variance in the size of TCR footprints, and examples of ectopic, rotated, or even reversed polarity of the TCR α and β chains [27, 28], there are no

On until off T cell response

Co-recognition models emphasize antigen specificity and a regulated ‘off until on’ mode of T cell response in which TCRs scan many cellular antigen complexes before contacting the rare cognate antigen. The extreme lipid polyspecificity in CD1-centric models predict that T cells do not require a rare, defined autoantigen. Instead T cells are directly activated by any APC expressing the correct CD1 protein. In addition to the in vitro studies reviewed above, evidence for CD1-directed

CD1-TCR contact as a rare and regulated event

MHC I is expressed on nearly all cells, and MHC II is broadly expressed on APCs and some epithelia. In contrast, CD1 proteins are comparatively rare and show regulated expression in the periphery. The constitutive expression of CD1a, CD1b, or CD1c, is mostly limited to individual APC types. CD1a is expressed mainly on epidermal Langerhans cells. CD1c is found on marginal zone B cells and the major population of classical dendritic cells, and CD1b, while rarely expressed on unactivated cells in

Fine-tuning the ‘on and off’ of CD1 autoreactivity

Certain CD1 ligands block the formation of stable TCR-CD1 complexes, pointing to a natural mechanism to limit T cell activation [17, 18•, 41]. Such ‘non-permissive ligands’ (sphingomyelin, phosphatidylcholine) generally have head groups that are larger than those on antigenic ligands (fatty acids, monoacylglycerols, squalene), suggesting that stearic hindrance of the TCR is the blocking mechanism. However, one structure of CD1a-sphingomyelin demonstrated that the ligand can interact with a

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank Ildiko van Rhijn and Sara Suliman for helpful comments and discussion. This work was supported by the National Institutes of Health (R01 AR048632 awarded to D. Branch Moody), the National Health and Medical Research Council, the Wellcome Trust, and the Australian Research Council. Jamie Rossjohn is supported by an ARC Laureate Fellowship. Rachel Cotton is supported by a Translation Accelerator Grant from the Human Skin Disease Resource Center at Brigham and Women's Hospital

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