醫(yī)學免疫學課件：Vγ9δ2 T Cell and Its Role in Cancer Immunotherapy

1、V92 T Cell and Its Application in Cancer ImmunotherapyOutline T cell92 T cell activationAntigensRecognition92 T cell effector function92 T cell related cancer immunotherapy T CellDiscovered between 1984 and 1987TCR chain & chainV(D)J recombination chain gene7th chromosome8V, 5J , 2C gene segments ch

2、ain gene14th chromosome6V, 3D, 3J, 1C gene segments Chain Legut, M., D.K. Cole and A.K. Sewell, The promise of gammadelta T cells and the gammadelta T cell receptor for cancer immunotherapy. Cell Mol Immunol, 2015. 12(6): p. 656-68. ChainLegut, M., D.K. Cole and A.K. Sewell, The promise of gammadelt

3、a T cells and the gammadelta T cell receptor for cancer immunotherapy. Cell Mol Immunol, 2015. 12(6): p. 656-68. T Cell SubsetsAccording to chainV1V2V92 most common, V23, V1.89, and J1 rearrangementsV3Migration and tissue locationTCR rearrangements determine V1T cells use to locate in bowel and epit

4、heliaV92 mostly locate in peripheral bloodcomprise 15% T cells in blood in healthy adults50-95% of T cells in blood92 T Cell AntigensPhosphoantigensPhosphoantigen identification from MEP pathway of isoprenoid biosynthesisBiosynthesis(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP,HDMAPP)isope

5、ntenyl pyrophosphate (IPP) dimethylallyl pyrophosphate (DMAPP)Synthetic phosphoantigensBromohydrin pyrophosphate(BrHPP,IPH101, Phosphostim)Ethyl pyrophosphate (EtPP) cHDMAPPGu, S., W. Nawrocka and E.J. Adams, Sensing of Pyrophosphate Metabolites by V9V 2 T Cells. Frontiers in Immunology, 2015. 5.MEP

6、 pathwaysM. Eberl, M. Hintz, A. Reichenberg, A.K. Kollas, J. Wiesner, H. Jomaa Microbial isoprenoid biosynthesis and human T cell activation FEBS Lett., 544 (2003), pp. 410IPP & DMAPPOverproduction Metabolically active tissues including tumor cells Inhibition of farnesyl pyrophosphate synthase (FPPS

7、) Aminobisphophonates(also known as nitrogen-containing bisphosphonates (N-bis) such as zoledronate, pamidronateAminated alkyl molecules such as isobutylamine92 T Cell RecoginitionNo MHC1995TCR-dependentNo direct interaction between PAgs and 92 TCRRequirement of cell-to-cell contact between 92 T cel

8、l and pAg-treated cell for stimulationSuggesting the presence of a target-cell associated ligand2005F1-ATPase PAgs could bind F1-ATPase in the form of a nucleotide derivative, increasing the efficiency of 92 T cell activation2010Antibody blocking of F1-ATPase not abrogate 92T cell recognitionOther m

9、olecules involved in PAg presentation2012Mouse anti-human butyrophilin-3A(BTN3A) antibody (clone 20.1), caused proliferation and expansion of 92 T cells PAgs and 20.1 antibody activated the same intracellular signalling pathways in the responding 92 T cellsIdentification of the butyrophilin-3A (BTN3

10、A) protein family as a key mediator in this processButyrophilin-3A(BTN3A)Known as CD277Type I membrane proteintwo immunoglobulin(Ig)-like extracellular domains (IgV and IgC)structural homology to the B7-superfamily of proteinsPresent in humans in three isoforms (BTN3A1, BTN3A2 and BTN3A3)A1 and A3 e

11、ach contain a B30.2 domain(also known as PRY/SPRY domains)Only the BTN3A1 isoform mediates pAg induced activationGu, S., W. Nawrocka and E.J. Adams, Sensing of Pyrophosphate Metabolites by V9V 2 T Cells. Frontiers in Immunology, 2015. 5.Direct PresentingExtracellular domain of BTN3A1 molecules as “a

12、ntigen-presenting” BTN3A1 molecules associate with pAg and “present” it directly to the 92 TCRLack of high-affinity binding of PAgs to the extracellular regions of BTN3A1Legut, M., D.K. Cole and A.K. Sewell, The promise of gammadelta T cells and the gammadelta T cell receptor for cancer immunotherap

13、y. Cell Mol Immunol, 2015. 12(6): p. 656-68.Inside-Out Signaling Mechanism BTN3A1 as a sensor of intracellular PAgs Binding of pAg intracellularly translated extracellularly for detection by the 92 TCRSandstrom, A., et al., The Intracellular B30.2 Domain of Butyrophilin 3A1 Binds Phosphoantigens to

14、Mediate Activation of Human V9V 2 T Cells. Immunity, 2014. 40(4): p. 490-500.Gu, S., W. Nawrocka and E.J. Adams, Sensing of Pyrophosphate Metabolites by V9V 2 T Cells. Frontiers in Immunology, 2015. 5.Intracellular domain B30.2a positively charged surface pocketbinding with phosphoantigensSandstrom,

15、 A., et al., The Intracellular B30.2 Domain of Butyrophilin 3A1 Binds Phosphoantigens to Mediate Activation of Human V9V 2 T Cells. Immunity, 2014. 40(4): p. 490-500.Mutagenesis of this pocket abrogated pAg binding and the ability of BTN3A1 to mediate 92 T cell stimulationB30.2 domains found in A1 a

16、nd A3 are highlyhomologous, with 87% amino acid identity between the two The intracellular region of A3, however, has a unique70 amino acid extension C-terminal to its B30.2 domainGu, S., W. Nawrocka and E.J. Adams, Sensing of Pyrophosphate Metabolites by V9V 2 T Cells. Frontiers in Immunology, 2015

17、. 5.Introduction of the B30.2 domain of BTN3A1 into the nonactivating isoform BTN3A3, confer PAg binding and 92 T cell stimulationSandstrom, A., et al., The Intracellular B30.2 Domain of Butyrophilin 3A1 Binds Phosphoantigens to Mediate Activation of Human V9V 2 T Cells. Immunity, 2014. 40(4): p. 49

18、0-500.Sandstrom, A., et al., The Intracellular B30.2 Domain of Butyrophilin 3A1 Binds Phosphoantigens to Mediate Activation of Human V9V 2 T Cells. Immunity, 2014. 40(4): p. 490-500.Sandstrom, A., et al., The Intracellular B30.2 Domain of Butyrophilin 3A1 Binds Phosphoantigens to Mediate Activation

19、of Human V9V 2 T Cells. Immunity, 2014. 40(4): p. 490-500.Immobilization/clustering of BTN3A1 Immobilization of BTN3A1 molecules Flourescence Recovery after Photobleaching (FRAP)During conversion of a cell from a non-stimulatory to stimulatory state Increasing the avidity for the 92 TCRConformationa

20、l change of the BTN3A1 extracellular domains from non-stimulatory (Dimer 2) to stimulatory (Dimer 1)Crystal structures of the BTN3A extracellular domainsTwo dimeric interfacesSymmetric V-shaped homodimer (Dimer 1) positioning the C-terminal transmembrane domains close togetherstimulatoryHead-to-tail

21、 homodimer with an asymmetric dimer interface (Dimer 2)BTN3A molecules to lay flat, parallel to the cell-surfacenon-stimulatoryGu, S., W. Nawrocka and E.J. Adams, Sensing of Pyrophosphate Metabolites by V9V 2 T Cells. Frontiers in Immunology, 2015. 5.Sandstrom, A., et al., The Intracellular B30.2 Do

22、main of Butyrophilin 3A1 Binds Phosphoantigens to Mediate Activation of Human V9V 2 T Cells. Immunity, 2014. 40(4): p. 490-500.BTN3A1 necessary but not sufficient for 92 T cell activation Primate-specific molecule or molecule(s) in directly activating through the 92 TCRTwo previous situations result

23、ing in the recruitment of an additional factor that directly engages the 92 TCRGu, S., W. Nawrocka and E.J. Adams, Sensing of Pyrophosphate Metabolites by V9V 2 T Cells. Frontiers in Immunology, 2015. 5.92 T Cell Co-receptorNatural killer receptorsToll-like receptorsFc receptors92 T Cell Effector Fu

24、nctionKilling infected and stressed target cells Driving inflammatory and wound healing processesPromoting survival of monocytes and neutrophilsInducing maturation of dendritic cells (DCs), Providing B cell help, and priming CD4+ and CD8+ T cellsTyler, C.J., et al., Human V9/V 2 T cells: Innate adap

25、tors of the immune system. Cellular Immunology, 2015. 296(1): p. 10-21.92 T Cell CytolysisMediated by TRAIL, FasL, adhesion DNAX accessory molecule-1Secretion of perforines and granzymesTake part on antibody-dependent cell-mediated cytotoxicity(Some 92 T -cells expressing CD16)IFN- , TNF-Kobayashi,

26、H. and Y. Tanaka, T Cell ImmunotherapyA Review. Pharmaceuticals, 2015. 8(1): p. 40-61.9 2 T Cell Clinical TrialsIn vivo expansionsystemic administration of phosphoantigens or N-bisinterleukin-2 (IL-2) for expandingKobayashi, H. and Y. Tanaka, T Cell ImmunotherapyA Review. Pharmaceuticals, 2015. 8(1)

27、: p. 40-61.Problems Activation-induced 92 T cell anergyDecrease in the number of peripheral blood 92 T cells after infusion of these stimulants Kobayashi, H. and Y. Tanaka, T Cell ImmunotherapyA Review. Pharmaceuticals, 2015. 8(1): p. 40-61.Ex vivo expansionexpand 92 T cells ex vivo using synthetic

28、phosphoantigens or N-bisadministration of cultured 92 T cells to the patientAdoptive transfer Wada, I., et al., Intraperitoneal injection of in vitro expanded Vgamma9Vdelta2 T cells together with zoledronate for the treatment of malignant ascites due to gastric cancer. Cancer Med, 2014. 3(2): p. 362

29、-75.Kobayashi, H. and Y. Tanaka, T Cell ImmunotherapyA Review. Pharmaceuticals, 2015. 8(1): p. 40-61.Kobayashi et al. reported reduced tumour growth in three of five Renal Cell Carcinoma (RCC) patients receiving adoptively transferred T cells. The authors then repeated this trial in 2011 using adopt

30、ively transferred T cells in combination with ZA and IL-2 therapy, and found reduced tumour growth in 11 of 11 RCC patientsNakajima et al. and Sakamoto et al., no clinical responses were reported in cohorts of patients with RCC or non-small cell lung cancer receiving adoptive transfer of in-vitrosti

31、mulated T cellsFutureLegut, M., D.K. Cole and A.K. Sewell, The promise of gammadelta T cells and the gammadelta T cell receptor for cancer immunotherapy. Cell Mol Immunol, 2015. 12(6): p. 656-68.References 1.Tyler, C.J., et al., Human V9/V2 T cells: Innate adaptors of the immune system. Cellular Imm

32、unology, 2015. 296(1): p. 10-21. 2.Kobayashi, H. and Y. Tanaka, T Cell ImmunotherapyA Review. Pharmaceuticals, 2015. 8(1): p. 40-61. 3.Sandstrom, A., et al., The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vgamma9Vdelta2 T cells. Immunity, 2014. 40(4): p. 490-500. 4.Legut, M., D.K. Cole and A.K. Sewell, The promise of gammadelta T cells and the gammadelta T cell receptor for cancer immunotherapy. Cell Mol Immunol, 2015. 12(6): p. 656-6