Atypical TRAV1-2 ^- T cell receptor recognition of the antigen-presenting molecule MR1.

Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE

Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology

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/metabolism

MR1 presents vitamin B-related metabolites to mucosal associated invariant T (MAIT) cells, which are characterized, in part, by the TRAV1-2 ⁺ αβ 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 β-chain of the D462-E4 TCR binds over the F'-pocket of MR1, whereby the complementarity-determining region (CDR) 3β loop surrounded and projected into the F'-pocket. Nevertheless, the CDR3β 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.
Competing Interests: Conflict of interest—J. R., J. M., L. L., and D. P. F. are named inventors on patent applications (PCT/AU2013/000742, WO2014005194) (PCT/AU2015/050148, WO2015149130) involving MR1 ligands for MR1-restricted MAIT cells owned by University of Queensland, Monash University, and University of Melbourne.

Nat Immunol. 2016 May;17(5):531-7. (PMID: 27043408)
J Immunol. 2013 Apr 1;190(7):3142-52. (PMID: 23447689)
Nat Commun. 2019 May 21;10(1):2243. (PMID: 31113973)
Immunol Cell Biol. 2020 Oct;98(9):770-781. (PMID: 32568415)
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21. (PMID: 20057044)
J Exp Med. 2013 Oct 21;210(11):2305-20. (PMID: 24101382)
Immunity. 2016 Jan 19;44(1):32-45. (PMID: 26795251)
J Synchrotron Radiat. 2018 May 1;25(Pt 3):885-891. (PMID: 29714201)
Nat Immunol. 2020 Apr;21(4):400-411. (PMID: 32123373)
Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):32-41. (PMID: 17164524)
J Immunol. 2018 Nov 15;201(10):2862-2871. (PMID: 30397170)
J Exp Med. 2014 Jul 28;211(8):1601-10. (PMID: 25049333)
Nature. 2014 May 15;509(7500):361-5. (PMID: 24695216)
Blood. 2011 Jan 27;117(4):1250-9. (PMID: 21084709)
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42. (PMID: 21460441)
J Exp Med. 2012 Apr 9;209(4):761-74. (PMID: 22412157)
Nat Immunol. 2010 Aug;11(8):701-8. (PMID: 20581831)
J Exp Med. 1993 Jul 1;178(1):1-16. (PMID: 8391057)
Immunol Cell Biol. 2018 Jul;96(6):607-617. (PMID: 29451704)
Proc Natl Acad Sci U S A. 2020 May 12;117(19):10465-10475. (PMID: 32341160)
Immunol Cell Biol. 2018 Jul;96(6):588-597. (PMID: 29393543)
Mucosal Immunol. 2017 Jan;10(1):35-45. (PMID: 27049062)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):133-44. (PMID: 20124693)
J Exp Med. 1999 Jun 21;189(12):1907-21. (PMID: 10377186)
Nat Immunol. 2017 Apr;18(4):402-411. (PMID: 28166217)
Science. 2019 Dec 20;366(6472):1522-1527. (PMID: 31857486)
Nat Commun. 2013;4:2142. (PMID: 23846752)
J Leukoc Biol. 2016 Jul;100(1):233-40. (PMID: 27034405)
Sci Immunol. 2018 Jul 13;3(25):. (PMID: 30006464)
Elife. 2017 May 18;6:. (PMID: 28518056)
J Exp Med. 2014 Jul 28;211(8):1585-600. (PMID: 25049336)
Nature. 2012 Nov 29;491(7426):717-23. (PMID: 23051753)
Nat Commun. 2016 Aug 16;7:12506. (PMID: 27527800)
Nat Immunol. 2020 Feb;21(2):178-185. (PMID: 31959982)
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32. (PMID: 15572765)
Nat Commun. 2014 May 15;5:3866. (PMID: 24832684)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702)
Nature. 2003 Mar 13;422(6928):164-9. (PMID: 12634786)
Immunol Cell Biol. 2018 Jul;96(6):573-587. (PMID: 29656544)
PLoS Biol. 2010 Jun 29;8(6):e1000407. (PMID: 20613858)

I01 BX000533 United States BX BLRD VA; R01 AI134790 United States AI NIAID NIH HHS; R01 AI148407 United States AI NIAID NIH HHS

Keywords: : Antigen presentation; MAIT; MHC-related molecule (MR1); T-cell receptor (TCR); atypical MAIT TCR; crystal structure; immunology; major histocompatibility complex (MHC); protein structure; receptor structure-function

PDB 4NQC; 5D7L; 4L4T

0 (5-(2-oxopropylideneamino)-6-d-ribitylaminouracil)
0 (Histocompatibility Antigens Class I)
0 (MR1 protein, human)
0 (Minor Histocompatibility Antigens)
0 (Receptors, Antigen, T-Cell, alpha-beta)
488-81-3 (Ribitol)
56HH86ZVCT (Uracil)

Date Created: 20200821 Date Completed: 20210223 Latest Revision: 20240410

20240410

PMC7573270

10.1074/jbc.RA120.015292

32817339