4 東京医科大学雑誌第 74 巻第 1 号雑学 T T T T major histocompatibility complex ; MHC 1 T T cell receptor ; TCR TCR 学 TCR 雑 TCR T 1.T T 2 MH

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1 3 741: 3-13, 2016 T TCR Imaging unveils spatiotemporal regulation of lymphocyte activation Discovery of the T cell signaling units TCR microclusters Tadashi YOKOSUKA Department of Immunology, Tokyo Medical University, School of Medicine T T 1 T T T 2030 T T T T B NK NKT :T : E - mail : yokosuka@tokyo - med.ac.jp 1

Department of Immunology, Tokyo Medical University, School of Medicine T T 1 T T T

2 4 東京医科大学雑誌第 74 巻第 1 号雑学 T T T T major histocompatibility complex ; MHC 1 T T cell receptor ; TCR TCR 学 TCR 雑 TCR T 1.T T 2 MHC TCR MHC 30 T ) µm TCR central - supramolecular activation clusterc - SMAC 1 2

3 横須賀 : 分子イメージングが拓く免疫細胞の時空間的制御機構 5 TCR く分子のperipheral - SMAC p - SMAC 細胞が分子のdistal - SMAC d - SMACの構 3 T 細胞ののの構が免疫 c - SMAC TCR グの T 細胞須構免疫が T 細胞細胞の 5 分のンング 1 分ののが 2.T TCR 免疫がの細構が的イーメンンの構免疫が T 細胞細胞のがくのく細胞イーメンン 2の細胞が MHC 分子ンの細胞 2 イーメンンのの T 細胞 T 細胞メンンT 細胞細分子ンGreen fluorescent protein ; GFPメ分子子的分子のがのーーののンく 4 細胞 nm のの細胞が分子がの免疫が TCR ググーグ分子のがT 細胞がイーメンン2030 の TCR/ CD3 が 1 のーのー T 細胞の 5 分 c - SMAC ーくTCR のー TCR のくンー Zap70Zeta - associated protein 70 kdaーが細胞ー分子 SLP - 76SH2 domain - containing leukocyte protein 76 kda TCR 4a 時のの TCR グ分子のグ T 細胞のグ TCR イー 5 ーー分子がーの 2030 グ分子 TCR/CD3 が c - SMAC 4b c - SMAC TCR が分のの機のd - SMACグ分子 TCR イーが的が T 細胞グ 5 3

T TCR 免疫がの細構が的イーメンンの構免疫が T 細胞細胞のがくのく細胞イーメンン 2の細胞が MHC 分子ンの細胞 2 イーメンンのの T 細胞 T 細胞メンンT 細胞細分子ンGreen fluorescent protein ; GFPメ分子子的分子のがのーーののンく 4 細胞 200

4 6 東京医科大学雑誌第 74 巻第 1 号 3 TCR/CD3 CD4 + T CD3ζ - GFP T 2 TCR/CD3 5 4 TCR at TCR/CD3 Zap70 SLP - 76 bc - SMAC d - SMAC Zap70 SLP CD28 T T T TCR T T CD28 inducible T cell costimulator ICOS 4 cytotoxic T - lymphocyte - associated protein 4 CTLA - 4 programmed death 1 PD TCR TCR TCR

CD28 T T T TCR T T CD28 inducible T cell costimulator ICOS 4 cytotoxic T -

5 横須賀 : 分子イメージングが拓く免疫細胞の時空間的制御機構 7 TCR グ mitogen - activated protein kinase MAPK ErkJNKp38 - NFAT nuclear factor - κb NF - κb phosphatidylinositol 3PI3ーンイングングー分 CD28 NF - κb のICOS IP3 ーグの的ーの的が分 CD28 ン CD80/CD86 c - SMAC NF - κb の 9)10 5a NF - κb の CD28 が Src ー分子の Lck ー protein kinase c θ PKCθ 11 ンCARD - containing MAGUK protein 1 Carma1ー 12 5b Carma1 の細胞 B 細胞ンのの Carma1 NF - κb のーの 1 ICOS ン ICOSL TCR イーイーの PI3 ー 4. が免疫の免疫イン T 細胞の制的が制 T 細胞の制が CTLA - 4 T 細胞の細胞細胞ン CD80/CD86CD28 のン CD28 ンCD28 グ制 5c CTLA - 4 子の T 細胞の免疫 5 CD28 NF - B CTLA - 4 aン CD80 のイー CD28 免疫の bcd28 NF - κb 構 PKCθ ccd80 の CD28 NF - κb CTLA - 4 分ー CTLA - 4 TCR 免疫 9)12 5

MAGUK protein 1 Carma1ー 12 5b Carma1 の細胞 B 細胞ンのの Carma1 NF - κb のーの 1 ICOS ン ICOSL TCR イーイーの PI3 ー 4.

6 8 東京医科大学雑誌第 74 巻第 1 号 2-3 第 PD - 1 T CTLA - 4 PD - 1 PD - 1 T CTLA - 4 PD - 1 CTLA - 4 TCR c - SMAC CD28 NF - κb 5d 12 PD - 1 PD - 1 ligand - 1/2 PD - L1/2 SH2 domain - containing tyrosine phosphatase 2 SHP2 TCR 6 13 CTLA - 4 abatacept balataceptctla - 4 CD28 CD80/CD86 CD28 NF - κb T CTLA - 4 ipilimumab 14 CTLA - 4 CD28 NF - B T PD - 1 nivolumab PD - 1 MPDL3280A 大 C PD - 1 SHP2 TCR T PD PD - 1 TCR a PD - L1 TCR c - SMAC PD - 1 bpd - 1 SHP2 13 6

CTLA - 4 abatacept balataceptctla - 4 CD28 CD80/CD86 CD28 NF - κb T CTLA - 4 ipilimumab 14 CTLA - 4 CD28 NF - B T

7 横須賀 : 分子イメージングが拓く免疫細胞の時空間的制御機構 9 がが細胞が PD - 1 ンくー T 細胞制 PD - 1 ン T 細胞制のー T 細胞制御 T 細胞細胞のが制 PD - 1 の的が PD - 1/ PD - L1 の免疫制ンが 5. 免疫細胞のが細胞くーーの T 細胞の TCR 免疫が細胞が細胞 T 細胞の分子インの細胞分子ンの細胞分子制御免疫イーの細胞分子がーー 7 T 細胞がくのが免疫 T 細胞が細胞 TCR グのくンのンのン IIA 15 分子インイーのーー 16 microtubule - organizing center ; MTOC T 細胞のが免疫のc - SMAC ののイーのーーくー T 細胞のーングンイ的細胞ーくの細胞細胞制御免疫の c - SMAC TCR/CD3 ーー TCR イー E3 ンーンインーーンE3 ンー Cbl B 細胞ンの子の SNP のCbl T 細胞 TCR イーのが TCR のがのののがンングンンメンのメンのの制 7 細胞免疫の 3 - D 構 7

免疫細胞のが細胞くーーの T 細胞の TCR 免疫が細胞が細胞 T 細胞の分子インの細胞分子ンの細胞分子制御免疫イーの細胞分子がーー 7 T 細胞がくのが免疫 T 細胞が細胞 TCR グのく

8 10 東京医科大学雑誌第 74 巻第 1 号 17 B c - SMAC B 6. T T T T T Transforming growth factor - βtgf - β T CTLA - 4 CTLA - 4 CD80/ CD86 CD28 CD28 NF - κb T 12 T CTLA - 4 PKCθ PKCη 18 PKCη T CTLA - 4 CD80/CD86 trogocytosis PD - 1 T T T C T PD - 1 PD - L1 PD T 7 8

9 横須賀 : 分子イメージングが拓く免疫細胞の時空間的制御機構 11 ンンの T 細胞 PD - 1 PD - 1 イー T 細胞の TCR グが PD - 1 PD - 1 ンの PD - 1 イーが時 T 細胞のが 13 のイメージング T 細胞のT 細胞細胞の免疫 TCR 制のイーが時間的空間的 8 TCR ーーグののの的制的的 T 細胞グのが TCR が T 細胞の機のB 細胞 natural killernk 細胞 NKT 細胞イーがイーがのメが分 19 免疫細胞 HIV イが CD4 CXCR5 イン CD4 + T 細胞 HTLV - 1 T 細胞 T 細胞のイの構的イのががイのイーが CTLA - 4 CTLA - 4 免疫ン PD - 1/PD - L1 ンののイー的のグ免疫細胞のグー的の細胞ののグ制御グ的のグののグのーのの機のメのンが 1 Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A : Three - dimensional segregation of supramolecular activation clusters in T cells.nature : 82-86, Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML : The immunological synapse : a molecular machine controlling T cell activation.science : , Dustin ML, Depoil D : New insights into the T cell synapse from single molecule techniques. Nature reviews.immunology 1110: , Tokunaga M, Imamoto N, Sakata - Sogawa K : Highly inclined thin illumination enables clear single - molecule imaging in cells.nat Methods 52: , Yokosuka T, Sakata - Sogawa K, Kobayashi W, Hiroshima M, Hashimoto - Tane A, Tokunaga M, Dustin ML, Saito T : Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP - 76.Nat Immunol 6 12: , Saito T, Yokosuka T : Immunological synapse and microclusters : the site for recognition and activation of T cells.curr Opin Immunol 183: , Yokosuka T, Saito T : The immunological synapse, TCR microclusters, and T cell activation.curr Top Microbiol Immunol 340 : , Sharpe AH : Mechanisms of costimulation.immunol Rev 2291: 5-11, Yokosuka T, Kobayashi W, Sakata - Sogawa K, Takamatsu M, Hashimoto - Tane A, Dustin ML, Tokunaga M, Saito T : Spatiotemporal regulation of T cell costimulation by TCR - CD28 microclusters and protein kinase C theta translocation.immunity 294: , Yokosuka T, Saito T : Dynamic regulation of T - cell costimulation through TCR - CD28 microclusters. Immunol Rev 229 : 27-40, Kong KF, Yokosuka T, Canonigo - Balancio AJ, Isakov N, Saito T, Altman A : A motif in the V3 domain of the kinase PKC - theta determines its localization in the immunological synapse and functions in T cells via association with CD28.Nat Immunol 1211: , Yokosuka T, Kobayashi W, Takamatsu M, Sakata - Sogawa K, Zeng H, Hashimoto - Tane A, Yagita H, Tokunaga M, Saito T : Spatiotemporal basis of CTLA - 4 costimulatory molecule - mediated negative regulation of T cell activation.immunity 333: , Yokosuka T, Takamatsu M, Kobayashi - Imanishi W, 9

4 免疫ン PD - 1/PD - L1 ンののイー的のグ免疫細胞のグー的の細胞ののグ制御グ的のグののグのーのの機のメのンが 1 Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A : Three - dimensional segregation of supramolecular

10 12 東京医科大学雑誌第 74 巻第 1 号 Hashimoto - Tane A, Azuma M, Saito T : Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2096: , Linsley PS, Nadler SG : The clinical utility of inhibiting CD28 - mediated costimulation. Immunol Rev 2291: , Ilani T, Vasiliver - Shamis G, Vardhana S, Bretscher A, Dustin ML : T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Nat Immunol 105: , Hashimoto - Tane A, Yokosuka T, Sakata - Sogawa K, Sakuma M, Ishihara C, Tokunaga M, Saito T : Dynein - driven transport of T cell receptor microclusters regulates immune synapse formation and T cell activation. Immunity 346: , Liang Y, Cucchetti M, Roncagalli R, Yokosuka T, Malzac A, Bertosio E, Imbert J, Nijman IJ, Suchanek M, Saito T, Wulfing C, Malissen B, Malissen M : The lymphoid lineage - specific actin - uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells. Nat Immunol 148: , Kong KF, Fu G, Zhang Y, Yokosuka T, Casas J, Canonigo - Balancio AJ, Becart S, Kim G, Yates JR, 3rd, Kronenberg M, Saito T, Gascoigne NR, Altman A : Protein kinase C - eta controls CTLA mediated regulatory T cell function. Nat Immunol 155: , Fleire SJ, Goldman JP, Carrasco YR, Weber M, Bray D, Batista FD : B cell ligand discrimination through a spreading and contraction response. Science : ,

Immunol Rev 2291: 307-321, 2009 15 Ilani T, Vasiliver - Shamis G, Vardhana S, Bretscher A, Dustin ML : T cell antigen receptor signaling and immunological synapse stability require myosin IIA.

11 横須賀 : 分子イメージングが拓く免疫細胞の時空間的制御機構 13 Imaging unveils spatiotemporal regulation of lymphocyte activation Discovery of the T cell signaling units TCR microclusters Tadashi YOKOSUKA Department of Immunology, Tokyo Medical University, School of Medicine Abstract Immune system is a higher - order network where various cells communicate each other and maintain the homeostasis of internal environments from invaders by identifying self and non - self or pathogenic and non - pathogenic.among a set of immune cells, T cells are important coordinators in this system to display clinical conditions, such as suppression of autoimmune diseases or allergy, rejection of transplants, and recognition and elimination of cancer cells.t cells recognize antigen peptides on MHCs via a solo receptor, T cell receptors TCRs, and introduce proliferation, differentiation, or apoptosis.although various biochemical approaches and structural analyses can contribute to unveil the mechanisms of antigen recognition and biological functions through a TCR, new imaging technologies remind us that T cells require a particular structure formed at the T cellantigen presenting cell interface, so called immunological synapse, for T cell activation regulation.we furthermore demonstrated that an immunological synapse is constructed by the clusters of several decades of TCRs and their downstream signaling molecules, TCR microcluster, which is an essential signaling unit for antigen recognition and T cell activation.our continuing studies further illustrate the spatiotemporal regulation of T cell activation not only by TCR microclusters but also by the other signaling clusters composed of positive or negative costimulatory receptors, phosphatases, degradation - related molecules, and so forth.microcluster becomes a commonly known concept for the signaling of lymphocytes bearing antigen - recognition receptors like B cells, NK cells, and NKT cells. Key words: T cell receptor, signal transduction, molecular imaging, immunological synapse, immune checkpoint 11

homeostasis of internal environments from invaders by identifying self and non - self or pathogenic and non - pathogenic.

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免疫Ⅱ 100 100 100 1990 127 DNA DNA DNA DNA hybridization DNA RNA DNA DNA 128 12 µδγαε 129 300 1,200 500 50012 4 24,000 1,20024,000 2.910 7 10 8 rejection major histocompatibility complex MHC MHC MHC 130 MHC

4 東 京 医 科 大 学 雑 誌 第 74 巻 第 1 号 雑 学 T T T T major histocompatibility complex ; MHC 1 T T cell receptor ; TCR TCR 学 TCR 雑 TCR T 1.T T 2 MH

4 東京医科大学雑誌第 74 巻第 1 号雑学 T T T T major histocompatibility complex ; MHC 1 T T cell receptor ; TCR TCR 学 TCR 雑 TCR T 1.T T 2 MH