title: Phosphoantigen Presentation to TCR γδ Cells, a Conundrum Getting Less Gray Zones.
abstract: The mechanistic requirements of antigen recognition by T cells expressing a γδ TCR has revealed important differences with those of αβ TCR cells and, despite impressive new data generated in the very recent years, they remain poorly understood. Based on the structure of the TCR chains and the tissue distribution, γδ cells are represented in a variety of populations. The major subset of human peripheral blood γδ cells express Vγ9Vδ2 TCR heterodimers and are all stimulated by phosphorylated metabolites (commonly called phosphoantigens). Phosphoantigens are molecules with a very small mass and only stimulate Vγ9Vδ2 cells in the presence of antigen-presenting cells, suggesting a strict requirement for dedicated antigen-presenting molecules. Recent studies have identified butyrophilin (BTN) 3A1 as the molecule necessary to stimulate Vγ9Vδ2 cells. BTN3A1 extracellular, transmembrane, and cytoplasmic domains have different functions, including cognate interaction with the Vγ9Vδ2 TCR, binding of the phosphoantigens, and interaction with cytoplasmic proteins. This review mainly discusses the known molecular mechanisms of BTN3A1-mediated antigen presentation to γδ cells and proposes a model of phosphoantigen presentation, which integrates past and recent studies.
authors: Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR) , Singapore , Singapore ; Department of Biomedicine, University of Basel , Basel , Switzerland.
authors: Gennaro
authors: G
authors: De Libero
authors: Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR) , Singapore , Singapore.
authors: Sze-Yi
authors: SY
authors: Lau
authors: Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR) , Singapore , Singapore ; Department of Biomedicine, University of Basel , Basel , Switzerland.
authors: Lucia
authors: L
authors: Mori
keywords: antigen presentation; butyrophilin 3A1; infection control; tumor surveillance; γδ TCR
references: Science. 2000 Jan 14;287(5451):314-6
references: 10634788
references: Proc Natl Acad Sci U S A. 1972 Jun;69(6):1508-13
references: 4338594
references: Immunol Today. 1995 Jul;16(7):316-8
references: 7576062
references: J Exp Med. 1989 May 1;169(5):1847-51
references: 2469770
references: Immunity. 2012 Sep 21;37(3):524-34
references: 22960222
references: Eur J Immunol. 2014 Sep;44(9):2571-6
references: 24890657
references: Blood. 2012 Sep 13;120(11):2269-79
references: 22767497
references: Trends Immunol. 2012 Jan;33(1):34-41
references: 22030238
references: J Immunol. 1989 Mar 15;142(6):1840-6
references: 2466078
references: Immunity. 2013 Dec 12;39(6):1032-42
references: 24239091
references: Eur J Immunol. 1989 Jul;19(7):1267-71
references: 2527158
references: J Immunol. 1995 Jun 1;154(11):5986-94
references: 7751641
references: J Exp Med. 1991 Jun 1;173(6):1311-22
references: 1827824
references: Curr Top Microbiol Immunol. 1991;173:235-8
references: 1833149
references: Eur J Immunol. 1993 Apr;23(4):804-8
references: 8384559
references: J Immunol. 1993 Mar 1;150(5):2046-55
references: 8094731
references: Nature. 1989 Jun 1;339(6223):342-3
references: 2786146
references: Immunity. 2005 Jan;22(1):71-80
references: 15664160
references: Immunity. 2000 Jan;12(1):51-60
references: 10661405
references: Biochem Pharmacol. 2014 Jun 1;89(3):301-12
references: 24680696
references: Cell. 1994 Jan 14;76(1):29-37
references: 8287478
references: Nature. 1989 Jul 27;340(6231):309-12
references: 2473405
references: Eur J Immunol. 2012 Sep;42(9):2505-10
references: 22829134
references: J Biol Chem. 2012 Jun 15;287(25):20986-95
references: 22549773
references: J Immunol. 1991 Nov 15;147(10):3353-9
references: 1658146
references: Annu Rev Immunol. 2004;22:817-90
references: 15032598
references: Clin Vaccine Immunol. 2013 Apr;20(4):530-9
references: 23389928
references: J Immunol. 1993 Aug 1;151(3):1214-23
references: 8393042
references: Science. 1994 Sep 23;265(5180):1869-71
references: 7916481
references: Nat Rev Immunol. 2014 Aug;14 (8):559-69
references: 25060581
references: Eur J Immunol. 1996 Mar;26(3):544-51
references: 8605919
references: J Exp Med. 2000 Mar 20;191(6):937-48
references: 10727456
references: J Biol Chem. 2009 Aug 14;284(33):22444-56
references: 19531472
references: Immunol Rev. 1991 Apr;120:89-115
references: 1830863
references: J Immunol. 1990 Jun 1;144(11):4156-62
references: 2111341
references: Nat Immunol. 2012 Sep;13(9):872-9
references: 22885985
references: Immunol Rev. 2007 Feb;215:59-76
references: 17291279
references: J Exp Med. 1989 Nov 1;170(5):1521-35
references: 2572670
references: J Exp Med. 1994 Jan 1;179(1):323-8
references: 8270877
references: EMBO J. 2006 Mar 22;25(6):1353-63
references: 16498413
references: J Immunol. 2003 Apr 1;170(7):3696-706
references: 12646635
references: J Biol Chem. 2001 May 25;276(21):18337-44
references: 11279081
references: Eur J Immunol. 2008 Aug;38(8):2200-9
references: 18624305
references: J Exp Med. 1988 Nov 1;168(5):1899-916
references: 2846743
references: Immunity. 1995 Oct;3(4):495-507
references: 7584140
references: J Clin Invest. 1992 Jan;89(1):308-14
references: 1345917
references: Immunity. 2014 Apr 17;40(4):490-500
references: 24703779
references: J Exp Med. 2003 Jan 20;197(2):163-8
references: 12538656
references: J Exp Med. 1997 Jan 6;185(1):91-7
references: 8996245
references: Nat Genet. 2008 May;40(5):656-62
references: 18408721
references: Eur J Immunol. 1995 Jul;25(7):2052-8
references: 7621879
references: Cell Mol Immunol. 2013 Jan;10(1):13-20
references: 23085946
references: J Exp Med. 1992 Dec 1;176(6):1785-9
references: 1460433
references: J Immunol. 2010 Jun 1;184(11):6209-22
references: 20483784
references: N Engl J Med. 1991 Mar 28;324(13):877-81
references: 1705662
references: Nature. 1995 May 11;375(6527):155-8
references: 7753173
references: J Cell Biol. 1981 Jun;89(3):485-94
references: 7019216
references: FEBS Lett. 2001 Dec 7;509(2):317-22
references: 11741609
references: J Immunol. 1991 Nov 15;147(10):3360-9
references: 1658147
references: Science. 1989 Aug 18;245(4919):746-9
references: 2528206
references: J Biol Chem. 2012 Sep 21;287(39):32780-90
references: 22846996
references: Eur J Immunol. 1990 Mar;20(3):703-6
references: 1690662
references: Eur J Immunol. 2004 Aug;34(8):2089-99
references: 15259006
references: Chem Biol. 2014 Aug 14;21(8):945-54
references: 25065532
references: J Immunol. 1994 Oct 1;153(7):3093-100
references: 8089488
references: Science. 1990 Jul 6;249(4964):67-9
references: 1695022
references: Nat Immunol. 2013 Nov;14(11):1137-45
references: 24076636
references: FASEB J. 2000 Sep;14(12):1669-70
references: 10973912
references: J Immunol. 2003 Nov 15;171(10):5027-33
references: 14607899
references: Int J Cancer. 1999 Mar 1;80(5):709-14
references: 10048972
references: Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2414-9
references: 21262824
references: J Immunol. 2003 Apr 1;170(7):3608-13
references: 12646624
references: Infect Immun. 2002 Aug;70(8):4019-27
references: 12117907
references: Nat Immunol. 2013 Sep;14 (9):908-16
references: 23872678
references: Mol Immunol. 2002 May;38(14):1051-61
references: 11955597
references: Eur J Immunol. 2001 May;31(5):1628-35
references: 11465120
references: Science. 2005 Apr 8;308(5719):227-31
references: 15821084
references: Nature. 2001 Jun 14;411(6839):820-4
references: 11459064
references: Science. 1990 Nov 30;250(4985):1269-73
references: 1978758
references: Elife. 2014 Sep 25;3:e03609
references: 25255099
references: Science. 1998 Mar 13;279(5357):1737-40
references: 9497295
references: Immunity. 1999 Jan;10(1):51-61
references: 10023770
references: Immunogenetics. 2014 Apr;66(4):243-54
references: 24526346
references: Nature. 1989 Oct 5;341(6241):447-50
references: 2477705