Structural Basis of Specificity and Cross-reactivity in T Cell Receptors Specific for Cytochrome C-I-E(k)

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2011 Apr 15

PMID 21490152

Citations 44

Authors

Evan W Newell

Lauren K Ely

Andrew C Kruse

Philip A Reay

Stephanie N Rodriguez

Aaron E Lin

Michael S Kuhns

K Christopher Garcia

Mark M Davis

Affiliations

Soon will be listed here.

Abstract

T cells specific for the cytochrome c Ag are widely used to investigate many aspects of TCR specificity and interactions with peptide-MHC, but structural information has long been elusive. In this study, we present structures for the well-studied 2B4 TCR, as well as a naturally occurring variant of the 5c.c7 TCR, 226, which is cross-reactive with more than half of possible substitutions at all three TCR-sensitive residues on the peptide Ag. These structures alone and in complex with peptide-MHC ligands allow us to reassess many prior mutagenesis results. In addition, the structure of 226 bound to one peptide variant, p5E, shows major changes in the CDR3 contacts compared with wild-type, yet the TCR V-region contacts with MHC are conserved. These and other data illustrate the ability of TCRs to accommodate large variations in CDR3 structure and peptide contacts within the constraints of highly conserved TCR-MHC interactions.

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References

Jameson S, Carbone F, Bevan M . Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells. J Exp Med. 1993; 177(6):1541-50. PMC: 2191028. DOI: 10.1084/jem.177.6.1541. View

Boniface J, Reich Z, Lyons D, Davis M . Thermodynamics of T cell receptor binding to peptide-MHC: evidence for a general mechanism of molecular scanning. Proc Natl Acad Sci U S A. 1999; 96(20):11446-51. PMC: 18053. DOI: 10.1073/pnas.96.20.11446. View

Ebert P, Richie Ehrlich L, Davis M . Low ligand requirement for deletion and lack of synapses in positive selection enforce the gauntlet of thymic T cell maturation. Immunity. 2008; 29(5):734-45. PMC: 3762485. DOI: 10.1016/j.immuni.2008.09.014. View

Matsui K, Boniface J, Steffner P, Reay P, Davis M . Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci U S A. 1994; 91(26):12862-6. PMC: 45540. DOI: 10.1073/pnas.91.26.12862. View

Fazilleau N, McHeyzer-Williams L, Rosen H, McHeyzer-Williams M . The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol. 2009; 10(4):375-84. PMC: 2712297. DOI: 10.1038/ni.1704. View

Weber K, Donermeyer D, Allen P, Kranz D . Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad Sci U S A. 2005; 102(52):19033-8. PMC: 1323173. DOI: 10.1073/pnas.0507554102. View

Ausubel L, Bieganowska K, Hafler D . Cross-reactivity of T-cell clones specific for altered peptide ligands of myelin basic protein. Cell Immunol. 1999; 193(1):99-107. DOI: 10.1006/cimm.1998.1447. View

Crawford F, Huseby E, White J, Marrack P, Kappler J . Mimotopes for alloreactive and conventional T cells in a peptide-MHC display library. PLoS Biol. 2004; 2(4):E90. PMC: 387264. DOI: 10.1371/journal.pbio.0020090. View

Kozono H, White J, Clements J, Marrack P, Kappler J . Production of soluble MHC class II proteins with covalently bound single peptides. Nature. 1994; 369(6476):151-4. DOI: 10.1038/369151a0. View

10.

Patten P, Gray N, Yang P, Marks C, Wedemayer G, Boniface J . The immunological evolution of catalysis. Science. 1996; 271(5252):1086-91. DOI: 10.1126/science.271.5252.1086. View

11.

Garcia K, Adams J, Feng D, Ely L . The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat Immunol. 2009; 10(2):143-7. PMC: 3982143. DOI: 10.1038/ni.f.219. View

12.

Cemerski S, Das J, Locasale J, Arnold P, Giurisato E, Markiewicz M . The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity. 2007; 26(3):345-55. PMC: 2763191. DOI: 10.1016/j.immuni.2007.01.013. View

13.

Hare B, Wyss D, Osburne M, Kern P, Reinherz E, Wagner G . Structure, specificity and CDR mobility of a class II restricted single-chain T-cell receptor. Nat Struct Biol. 1999; 6(6):574-81. DOI: 10.1038/9359. View

14.

. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr. 1994; 50(Pt 5):760-3. DOI: 10.1107/S0907444994003112. View

15.

Brunger A . Version 1.2 of the Crystallography and NMR system. Nat Protoc. 2007; 2(11):2728-33. DOI: 10.1038/nprot.2007.406. View

16.

Harkiolaki M, Holmes S, Svendsen P, Gregersen J, Jensen L, McMahon R . T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity. 2009; 30(3):348-57. DOI: 10.1016/j.immuni.2009.01.009. View

17.

Hayashi Y, Tsukumo S, Shiota H, Kishihara K, Yasutomo K . Antigen-specific T cell repertoire modification of CD4+CD25+ regulatory T cells. J Immunol. 2004; 172(9):5240-8. DOI: 10.4049/jimmunol.172.9.5240. View

18.

Ebert P, Jiang S, Xie J, Li Q, Davis M . An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat Immunol. 2009; 10(11):1162-9. PMC: 3762483. DOI: 10.1038/ni.1797. View

19.

Colf L, Bankovich A, Hanick N, Bowerman N, Jones L, Kranz D . How a single T cell receptor recognizes both self and foreign MHC. Cell. 2007; 129(1):135-46. DOI: 10.1016/j.cell.2007.01.048. View

20.

Clements C, Kjer-Nielsen L, Macdonald W, Brooks A, Purcell A, McCluskey J . The production, purification and crystallization of a soluble heterodimeric form of a highly selected T-cell receptor in its unliganded and liganded state. Acta Crystallogr D Biol Crystallogr. 2002; 58(Pt 12):2131-4. DOI: 10.1107/s0907444902015482. View