title: Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity.
abstract: Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, Oxfordshire, United Kingdom.
authors.forename: Himadri
authors.initials: H
authors.lastname: Mukhopadhyay
authors.forename: Shaun-Paul
authors.initials: SP
authors.lastname: Cordoba
authors.forename: Philip K
authors.initials: PK
authors.lastname: Maini
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Omer
authors.initials: O
authors.lastname: Dushek
mesh_terms: D000818:Animals; D006801:Humans; D018448:Models, Immunological; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods*
chemical_list: D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases
references.citation: J Immunol. 1998 Jul 1;161(1):375-84
references.pmid: 9647246
references.citation: Biophys J. 2011 Mar 2;100(5):1189-97
references.pmid: 21354391
references.citation: Curr Opin Immunol. 2009 Apr;21(2):215-23
references.pmid: 19327974
references.citation: Nat Rev Immunol. 2012 Mar 22;12(4):269-81
references.pmid: 22437939
references.citation: Front Immunol. 2012 Jan 10;2:91
references.pmid: 22566880
references.citation: Proc Natl Acad Sci U S A. 1981 Nov;78(11):6840-4
references.pmid: 6947258
references.citation: EMBO J. 1992 Feb;11(2):559-67
references.pmid: 1537335
references.citation: J Biol Chem. 1993 Mar 15;268(8):5886-93
references.pmid: 8383678
references.citation: Immunity. 2010 Jun 25;32(6):766-77
references.pmid: 20541955
references.citation: J Exp Med. 2011 Nov 21;208(12):2545-60
references.pmid: 22084409
references.citation: Cold Spring Harb Perspect Biol. 2010 Jun;2(6):a002485
references.pmid: 20516133
references.citation: Eur J Immunol. 1996 May;26(5):1063-8
references.pmid: 8647168
references.citation: Immunol Rev. 2009 Nov;232(1):7-21
references.pmid: 19909352
references.citation: Nature. 2009 Jul 9;460(7252):274-7
references.pmid: 19536158
references.citation: J Biol Chem. 2008 Mar 21;283(12):7338-45
references.pmid: 18204097
references.citation: Mol Cell. 2011 Sep 2;43(5):723-37
references.pmid: 21884975
references.citation: Biophys J. 2010 Apr 21;98(8):1396-407
references.pmid: 20409458
references.citation: Biophys J. 2009 Apr 8;96(7):2604-23
references.pmid: 19348745
references.citation: Annu Rev Immunol. 2009;27:591-619
references.pmid: 19132916
references.citation: Biophys J. 2008 Mar 15;94(6):1995-2006
references.pmid: 18055537
references.citation: J Exp Med. 1995 Jan 1;181(1):375-80
references.pmid: 7528772
references.citation: Immunity. 2007 Sep;27(3):421-3
references.pmid: 17892852
references.citation: Biophys J. 2010 Sep 22;99(6):L41-3
references.pmid: 20858409
references.citation: Nat Rev Immunol. 2011 Jan;11(1):47-55
references.pmid: 21127503
references.citation: Cell. 2009 Jan 23;136(2):337-51
references.pmid: 19167334
references.citation: J Immunol. 2003 Apr 1;170(7):3769-81
references.pmid: 12646643
references.citation: PLoS Biol. 2005 Nov;3(11):e356
references.pmid: 16231973
references.citation: FEBS J. 2009 Jun;276(12):3177-98
references.pmid: 19438722
references.citation: J Exp Med. 1993 Apr 1;177(4):1093-103
references.pmid: 8459204
references.citation: J Biol Chem. 1998 Jan 9;273(2):729-35
references.pmid: 9422724
references.citation: Methods Mol Biol. 2009;500:113-67
references.pmid: 19399430
references.citation: J Cell Biol. 2004 Feb 2;164(3):353-9
references.pmid: 14744999
references.citation: Immunol Rev. 2012 Nov;250(1):258-76
references.pmid: 23046135
references.citation: Cell. 2008 Nov 14;135(4):702-13
references.pmid: 19013279
references.citation: Blood. 2011 Jun 2;117(22):6012-23
references.pmid: 21464369
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19323-8
references.pmid: 22084078
references.citation: Science. 1998 Jul 24;281(5376):572-5
references.pmid: 9677202
references.citation: Proc Natl Acad Sci U S A. 1995 May 23;92(11):5106-10
references.pmid: 7761456
references.citation: Nat Struct Biol. 2000 Nov;7(11):1023-6
references.pmid: 11062556
references.citation: J Theor Biol. 2008 Sep 7;254(1):110-22
references.pmid: 18556025
references.citation: Eur J Immunol. 1997 Nov;27(11):3010-4
references.pmid: 9394831
references.citation: J Cell Biochem. 1996 Oct;63(1):94-103
references.pmid: 8891907
references.citation: Sci Signal. 2011 Jun 07;4(176):ra39
references.pmid: 21653229
references.citation: J Immunol. 2001 Jan 1;166(1):182-7
references.pmid: 11123291
references.citation: Nat Immunol. 2008 Jun;9(6):658-66
references.pmid: 18469818
references.citation: Nat Immunol. 2000 Oct;1(4):322-8
references.pmid: 11017104
references.citation: J Mol Biol. 1965 May;12:88-118
references.pmid: 14343300