ABSTRACT
Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we provide a basis for how a type II NKT cell TCR, XV19, recognized CD1d-sulfatide. The XV19 TCR bound orthogonally above the A' pocket of CD1d, in contrast to the parallel docking of type I NKT cell TCRs over the F' pocket of CD1d. At the XV19 TCR-CD1d-sulfatide interface, the TCRα and TCRß chains sat centrally on CD1d, where the malleable CDR3 loops dominated interactions with CD1d-sulfatide. Accordingly, we highlight the diverse mechanisms by which NKT cell TCRs can bind CD1d and account for the distinct antigen specificity of type II NKT cells.
Subject(s)
Antigens, CD1d/immunology , Killer Cells, Natural/immunology , Receptors, Antigen, T-Cell, alpha-beta/chemistry , Sulfoglycosphingolipids/immunology , T-Lymphocyte Subsets/immunology , Animals , Antigens, CD1d/chemistry , Crystallization , Killer Cells, Natural/chemistry , Lymphocyte Activation , Mice , Polymerase Chain Reaction , Protein Structure, Quaternary , Receptors, Antigen, T-Cell, alpha-beta/immunology , Sulfoglycosphingolipids/chemistry , Surface Plasmon Resonance , T-Lymphocyte Subsets/chemistryABSTRACT
MR1 presents vitamin B-related metabolites to mucosal associated invariant T (MAIT) cells, which are characterized, in part, by the TRAV1-2+ αß T cell receptor (TCR). In addition, a more diverse TRAV1-2- MR1-restricted T cell repertoire exists that can possess altered specificity for MR1 antigens. However, the molecular basis of how such TRAV1-2- TCRs interact with MR1-antigen complexes remains unclear. Here, we describe how a TRAV12-2+ TCR (termed D462-E4) recognizes an MR1-antigen complex. We report the crystal structures of the unliganded D462-E4 TCR and its complex with MR1 presenting the riboflavin-based antigen 5-OP-RU. Here, the TRBV29-1 ß-chain of the D462-E4 TCR binds over the F'-pocket of MR1, whereby the complementarity-determining region (CDR) 3ß loop surrounded and projected into the F'-pocket. Nevertheless, the CDR3ß loop anchored proximal to the MR1 A'-pocket and mediated direct contact with the 5-OP-RU antigen. The D462-E4 TCR footprint on MR1 contrasted that of the TRAV1-2+ and TRAV36+ TCRs' docking topologies on MR1. Accordingly, diverse MR1-restricted T cell repertoire reveals differential docking modalities on MR1, thus providing greater scope for differing antigen specificities.
Subject(s)
Histocompatibility Antigens Class I/metabolism , Minor Histocompatibility Antigens/metabolism , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Amino Acid Sequence , Antigen Presentation , Binding Sites , Crystallography, X-Ray , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Humans , Minor Histocompatibility Antigens/chemistry , Minor Histocompatibility Antigens/genetics , Molecular Docking Simulation , Protein Refolding , Protein Structure, Tertiary , Receptors, Antigen, T-Cell, alpha-beta/chemistry , Receptors, Antigen, T-Cell, alpha-beta/genetics , Ribitol/analogs & derivatives , Ribitol/chemistry , Ribitol/metabolism , Surface Plasmon Resonance , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Uracil/analogs & derivatives , Uracil/chemistry , Uracil/metabolismABSTRACT
The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections. MR1R9H was unable to present the potent microbially derived MAIT cell stimulatory ligand. The MR1R9H crystal structure revealed that the stimulatory ligand cannot bind due to the mutation lying within, and causing structural perturbation to, the ligand-binding domain of MR1. While MR1R9H could bind and be up-regulated by a MAIT cell inhibitory ligand, the patient lacked circulating MAIT cells. This shows the importance of the stimulatory ligand for MAIT cell selection in humans. The patient had an expanded γδ T cell population, indicating a compensatory interplay between these unconventional T cell subsets.
Subject(s)
Histocompatibility Antigens Class I/genetics , Intraepithelial Lymphocytes/immunology , Minor Histocompatibility Antigens/genetics , Mucosal-Associated Invariant T Cells , Primary Immunodeficiency Diseases/genetics , Humans , Point Mutation , Primary Immunodeficiency Diseases/immunologyABSTRACT
T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I-like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR-MR1-antigen complex starkly contrasts with all other TCR-MHC and TCR-MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.
Subject(s)
Antigen Presentation , Histocompatibility Antigens Class I/immunology , Minor Histocompatibility Antigens/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Crystallography, X-Ray , HEK293 Cells , Histocompatibility Antigens Class I/chemistry , Humans , Minor Histocompatibility Antigens/chemistry , Protein Domains , Receptors, Antigen, T-Cell, gamma-delta/chemistryABSTRACT
The mucosal-associated invariant T-cell antigen receptor (MAIT TCR) recognizes MR1 presenting vitamin B metabolites. Here we describe the structures of a human MAIT TCR in complex with human MR1 presenting a non-stimulatory ligand derived from folic acid and an agonist ligand derived from a riboflavin metabolite. For both vitamin B antigens, the MAIT TCR docks in a conserved manner above MR1, thus acting as an innate-like pattern recognition receptor. The invariant MAIT TCR α-chain usage is attributable to MR1-mediated interactions that prise open the MR1 cleft to allow contact with the vitamin B metabolite. Although the non-stimulatory antigen does not contact the MAIT TCR, the stimulatory antigen does. This results in a higher affinity of the MAIT TCR for a stimulatory antigen in comparison with a non-stimulatory antigen. We formally demonstrate a structural basis for MAIT TCR recognition of vitamin B metabolites, while illuminating how TCRs recognize microbial metabolic signatures.