title: Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner.
abstract: TCR (T-cell receptor) recognition of antigenic peptides bound and presented by MHC (major histocompatibility complex) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide-MHC complexes weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Furthermore, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. In the present study, we examined how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the Tax peptide [HTLV (human T-cell lymphotropic virus)-1 Tax(11-19)] enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with the A6 TCR independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, we probed the mechanism of fluorine's effect on TCR binding and we conclude that our results were most consistent with a 'polar hydrophobicity' mechanism, rather than a purely hydrophobic- or electrostatic-based mechanism. This finding should have an impact on other attempts to alter molecular recognition with fluorine.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Piepenbrink
authors.forename: Oleg Y
authors.initials: OY
authors.lastname: Borbulevych
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Sommese
authors.forename: John
authors.initials: J
authors.lastname: Clemens
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Armstrong
authors.forename: Clare
authors.initials: C
authors.lastname: Desmond
authors.forename: Priscilla
authors.initials: P
authors.lastname: Do
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
mesh_terms: D005461:Fluorine / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D016356:Gene Products, tax / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006680:HLA Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D014765:Viral Vaccines / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
chemical_list: D016356:Gene Products, tax; D006680:HLA Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014765:Viral Vaccines; C514970:tax protein, Human T-lymphotrophic virus 1; D005461:Fluorine
references.citation: Nat Biotechnol. 2005 Mar;23(3):349-54
references.pmid: 15723046
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5387-92
references.pmid: 10779548
references.citation: Nature. 1996 Nov 14;384(6605):134-41
references.pmid: 8906788
references.citation: Immunity. 2000 Oct;13(4):529-38
references.pmid: 11070171
references.citation: Biochem J. 2008 Oct 15;415(2):183-96
references.pmid: 18800968
references.citation: Chembiochem. 2004 May 3;5(5):614-21
references.pmid: 15122632
references.citation: Immunity. 2000 Oct;13(4):475-84
references.pmid: 11070166
references.citation: Chembiochem. 2004 May 3;5(5):622-7
references.pmid: 15122633
references.citation: Proteins. 2009 Mar;74(4):948-60
references.pmid: 18767161
references.citation: Biophys J. 2007 Jul 15;93(2):597-609
references.pmid: 17449678
references.citation: Immunity. 1998 Apr;8(4):403-11
references.pmid: 9586631
references.citation: J Mol Biol. 2005 Feb 18;346(2):533-50
references.pmid: 15670602
references.citation: PLoS One. 2008;3(12):e3938
references.pmid: 19079589
references.citation: J Virol. 1996 Feb;70(2):843-51
references.pmid: 8551623
references.citation: Semin Cancer Biol. 2007 Aug;17(4):317-29
references.pmid: 17651986
references.citation: Science. 2007 Sep 28;317(5846):1881-6
references.pmid: 17901324
references.citation: Immunity. 1999 Jul;11(1):45-56
references.pmid: 10435578
references.citation: J Mol Biol. 2006 Oct 13;363(1):228-43
references.pmid: 16962135