Kegg Pathway: T cell receptor signaling pathway

KEGG ID: 04660

Reference Diagram

KEGG Diagram for T cell receptor signaling pathway

Rat

There are 91 IPI Records from this pathway found in Rattus norvegicus.

Location of T cell receptor signaling pathway proteins on Rat Genome

IPI Record Position
1: Akt1 6:137640482-137657552
2: Akt2 1:82686233-82726544
3: Akt3 13:92807672-92924984
4: Bcl10 2:243932330-244126396
5: Card11_predicted 12:14187395-14228930
6: Cblb 11:49690402-49856762
7: Cblc 1:79092830-79108167
8: Cd28 9:59342273-59367743
9: Cd3d 8:47932212-47936744
10: Cd3e_predicted 8:47947815-47958309
11: Cd3g 8:47923964-47930555
12: Cd3z 13:81515440-81598548
13: Cd4 4:160988512-161014038
14: Cd40lg X:141925019-141937183
15: Cd8a 4:104589928-104594159
16: Cd8b 4:104536493-104549185
17: Cdc42 5:156106131-156143040
18: Cdk4 7:67016944-67018905
19: Chp 3:106066389-106101638
20: Chuk_predicted 1:249122847-249157179
21: Csf2 10:39665850-39667831
22: Ctla4 9:59495773-59501300
23: Fos 6:109559154-109562546
24: Fyn 20:43501853-43695567
25: Grap2 7:118906407-118930992
26: Grb2 10:105722014-105818649
27: Hras 1:201385708-201388983
28: Icos :-
29: Ifng 7:57621754-57625792
30: Ikbkb 16:73805082-73858088
31: Ikbkg X:160407166-160420190
32: Il10 13:43953859-43958332
33: Il2 2:123655005-123659709
34: Il4 10:39074582-39080134
35: Il5 10:39177783-39180657
36: Itk_predicted 10:31455977-31518075
37: Jun 5:115359397-115360401
38: Kras 4:182869242-182895106
39: Lat 1:185450155-185455180
40: Lck 5:148707498-148718474
41: Lcp2 10:19019978-19066754
42: Malt1_predicted 18:61647647-61759718
43: Map3k14_predicted 10:92406829-92430131
44: Map3k8 17:61910179-61930459
45: Nck1_predicted 8:105346331-105361312
46: Nck2_predicted 9:42650068-42776967
47: Nfat5_predicted 19:37088893-37241536
48: Nfatc2_predicted 3:159654343-159773666
49: Nfatc3_predicted 19:35907874-35979801
50: Nfatc4 15:33969620-33978926
51: Nfkb1 2:233091020-233187501
52: Nfkb2 1:251521559-251527815
53: Nfkbia 6:75729302-75732474
54: Nfkbib 1:83865440-83873010
55: Nras 2:198292616-198302308
56: Pak1 1:155057622-155174714
57: Pak2 11:70529961-70588515
58: Pak3 X:34734814-34842093
59: Pak4_predicted 1:83671618-83718945
60: Pak6_predicted 3:105184040-105192149
61: Pak7_predicted 3:124152031-124457583
62: Pdcd1_predicted 9:93173522-93185623
63: Pdk1 3:54292076-54319242
64: Pik3ca 2:118640277-118670170
65: Pik3cb 8:103886682-103957112
66: Pik3cd_predicted 5:166735338-166750186
67: Pik3cg_predicted 6:50444793-50477111
68: Pik3r1 2:32602673-32675350
69: Pik3r2 16:19171101-19179650
70: Pik3r3 5:136497494-136566473
71: Plcg1 3:151522949-151565985
72: Ppp3ca 2:234333405-234408670
73: Ppp3cb 15:4003159-4022737
74: Ppp3cc 15:50616841-50666010
75: Ppp3r1 14:98047333-98131590
76: Ppp3r2 5:66423374-66424371
77: Ptpn6 4:160843701-160856821
78: Ptprc 13:51247016-51357790
79: Rasgrp1 3:103371879-103433010
80: RGD1560225_predicted 18:77531419-77593552
81: RGD1563261_predicted 10:55182226-55247889
82: RGD1565941_predicted 2:204981254-205324562
83: Rhoa :-
84: Slc35b2 9:11044112-11050948
85: Sos1 6:3310823-3394313
86: Sos2 6:91610826-91722481
87: Tec 14:37798503-37865206
88: Tnf 20:3661000-3663618
89: Vav1 :-
90: Vav2_predicted 3:6155687-6347206
91: Zap70 9:35693089-35715071

Mouse

There are 91 IPI Records from this pathway found in Mus musculus.

Location of T cell receptor signaling pathway proteins on Mouse Genome

IPI Record Position
1: Akt1 :-
2: Akt2 7:27300516-27348213
3: Akt3 1:178862039-178967772
4: Bcl10 3:145861736-145871669
5: Card11 5:141125799-141165891
6: Cbl 9:43900257-43985041
7: Cblb 16:51952371-52127389
8: Cblc 7:18939488-18955304
9: Cd247 1:167625393-167705797
10: Cd28 :-
11: Cd3d 9:44732876-44737418
12: Cd3e 9:44749738-44760585
13: Cd3g 9:44720683-44731421
14: Cd4 6:124830325-124853807
15: Cd40lg X:53558927-53570826
16: Cd8a 6:71303062-71307116
17: Cd8b1 6:71252366-71263639
18: Cdc42 4:136591778-136629755
19: Cdk4 10:126466564-126470344
20: Chuk 19:44126647-44160756
21: Csf2 11:54090687-54093065
22: Ctla4 1:60853571-60860377
23: Fos 12:86363004-86366372
24: Fyn 10:39059219-39254797
25: Grap2 15:80399849-80476017
26: Grb2 11:115460216-115524687
27: Hras1 7:141040427-141045314
28: Icos 1:60922460-60944866
29: Ifng 10:117844040-117848885
30: Ikbkb 8:24124758-24172108
31: Ikbkg X:70677332-70704240
32: Il10 1:132847393-132852516
33: Il2 3:37312271-37317502
34: Il4 11:53455891-53462067
35: Il5 11:53564217-53568526
36: IPI00678029 :-
37: Itk 11:46168576-46232916
38: Jun 4:94542255-94544189
39: Kras 6:145173866-145207390
40: Lat 7:126154975-126160691
41: Lck 4:129050653-129075945
42: Lcp2 11:33947144-33992281
43: Malt1 18:65556332-65604192
44: Map3k14 11:103035854-103083835
45: Map3k8 18:4331325-4352951
46: Nck1 9:100304355-100355405
47: Nck2 1:43390297-43515060
48: Nfat5 8:110182688-110268637
49: Nfatc1 18:80797750-80875130
50: Nfatc2 2:168167615-168292860
51: Nfatc3 8:108948972-109017574
52: Nfatc4 14:54779079-54788014
53: Nfkb1 3:135292997-135605172
54: Nfkb2 19:46358111-46365401
55: Nfkbia 12:56407731-56410725
56: Nfkbib 7:28467011-28475284
57: Nfkbie 17:45019297-45026752
58: Nras 3:103187290-103196967
59: Pak1 7:97718145-97787562
60: Pak2 16:31937610-31999020
61: Pak3 X:138765079-139038221
62: Pak4 7:28267579-28277068
63: Pak6 2:118355211-118389459
64: Pak7 2:135773338-136079379
65: Pdcd1 1:95868708-95882959
66: Pdk1 2:71674063-71702840
67: Pik3ca 3:32627755-32654380
68: Pik3cb 9:98847754-98949439
69: Pik3cd 4:148492970-148542498
70: Pik3cg 12:32758720-32793858
71: Pik3r1 13:102781018-102868441
72: Pik3r2 8:73697168-73705691
73: Pik3r3 4:115719846-115800988
74: Pik3r5 11:68248320-68314041
75: Plcg1 2:160422751-160467201
76: Ppp3ca 3:136608220-136874773
77: Ppp3cb 14:19288592-19335096
78: Ppp3cc 14:68953164-69002587
79: Ppp3r1 :-
80: Ppp3r2 4:49699847-49703083
81: Prkcq 2:11090235-11219079
82: Ptpn6 6:124686727-124698484
83: Ptprc 1:139879826-139991716
84: Rasgrp1 2:116971424-117034442
85: Rhoa 9:108164298-108196026
86: Sos1 17:80306507-80388261
87: Sos2 12:70502371-70576665
88: Tec 5:73034869-73147618
89: Tnf 17:34807442-34810048
90: Vav1 17:56964450-57013288
91: Vav2 2:27084113-27249042
92: Vav3 3:109468739-109813750
93: Zap70 1:36706371-36727362

Human

There are 91 IPI Records from this pathway found in Homo sapiens.

Location of T cell receptor signaling pathway proteins on Human Genome

IPI Record Position
1: AKT1 14:104306734-104333125
2: AKT2 19:45430084-45483036
3: AKT3 1:241718158-242080053
4: BCL10 1:85504519-85516359
5: CARD11 7:2912309-3050025
6: CBL 11:118582200-118684066
7: CBLB 3:106859799-107070577
8: CBLC 19:49972966-49995736
9: CD247 1:165666501-165754471
10: CD28 2:204279443-204310801
11: CD3D 11:117715001-117718669
12: CD3E 11:117680662-117692096
13: CD3G 11:117720317-117729979
14: CD4 12:6769005-6800233
15: CD40LG X:135558002-135570215
16: CD8A 2:86865245-86871578
17: CD8B 2:86895973-86942549
18: CDC42 1:22235157-22292024
19: CDK4 12:56428272-56432431
20: CHP 15:39310729-39361369
21: CSF2 5:131437382-131439758
22: CTLA4 2:204440756-204446928
23: FOS 14:74815284-74818685
24: FYN 6:112088228-112301348
25: GRAP2 22:38627080-38698204
26: GRB2 17:70825753-70913384
27: HRAS 11:522243-525572
28: ICOS 2:204509716-204534541
29: IFNG 12:66834816-66839790
30: IKBKB 8:42247986-42309130
31: IKBKG X:153423653-153446455
32: IL10 1:205007570-205012462
33: IL2 4:123592080-123597339
34: IL4 5:132037272-132046267
35: IL5 5:131905035-131907113
36: ITK 5:156540432-156614687
37: JUN 1:59019048-59022587
38: KRAS 12:25249449-25295121
39: LAT :-
40: LCK 1:32489480-32524353
41: LCP2 5:169607667-169657400
42: MALT1 18:54489598-54568350
43: MAP3K14 17:40696278-40750148
44: MAP3K8 10:30762872-30790768
45: NCK1 3:138063763-138150657
46: NCK2 2:105727786-105877137
47: NFAT5 16:68156498-68296054
48: NFATC1 18:75256760-75390310
49: NFATC2 20:49441083-49592665
50: NFATC3 16:66676845-66818301
51: NFATC4 14:23907094-23918645
52: NFKB1 4:103641518-103757506
53: NFKB2 10:104144320-104152271
54: NFKBIA 14:34940475-34943703
55: NFKBIB 19:44082455-44091371
56: NFKBIE 6:44333881-44341503
57: NRAS 1:115048613-115102147
58: PAK1 11:76710709-76862581
59: PAK2 3:197951312-198043749
60: PAK3 X:110226244-110350815
61: PAK4 19:44308260-44361886
62: PAK6 15:38319361-38356979
63: PAK7 20:9466036-9767689
64: PDCD1 2:242440711-242449731
65: PDK1 2:173129025-173172108
66: PIK3CA 3:180349005-180435189
67: PIK3CB 3:139856921-139960875
68: PIK3CD 1:9634390-9711564
69: PIK3CG 7:106292977-106334801
70: PIK3R1 5:67547360-67633403
71: PIK3R2 19:18125016-18142343
72: PIK3R3 1:46278399-46371054
73: PIK3R5 17:8722953-8756559
74: PLCG1 20:39199291-39237775
75: PPP3CA 4:102163610-102487376
76: PPP3CB 10:74866192-74925765
77: PPP3CC 8:22354541-22454580
78: PPP3R1 :-
79: PPP3R2 9:103393718-103397104
80: PRKCQ 10:6509111-6662269
81: PTPN6 12:6930763-6940740
82: PTPRC 1:196874424-196993035
83: RASGRP1 15:36567590-36644224
84: RHOA 3:49371585-49424530
85: SOS1 2:39066469-39201067
86: SOS2 14:49654812-49767751
87: TEC 4:47832557-47966638
88: TNF 6:31678016-31680778
89: VAV1 19:6723722-6808371
90: VAV2 9:135616837-135847547
91: VAV3 1:107915305-108309108
92: ZAP70 2:97696461-97722755

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Recent Literature

Lysine 63 PolyubiquiTinaTion in ImmunoTherapy and in Cancer-promoTing InflammaTion.

TTp://www.hubmed.org/fullTexT.cgi?uids=19887490">Clin Cancer Res. 2009 Nov 3;
MarTinez-Forero I, RouzauT A, Palazon A, DubroT J, Melero I

CovalenT and reversible posT-TranslaTional modificaTions of proTeins are a common Theme in signaling. UbiquiTin conjugaTion was originally described To TargeT proTeins To proTeasomal degradaTion by ubiquiTin polymerizaTion involving lysine (K) 48 residues. DifferenTly linked polymers of polyubiquiTin have been found ThaT modify proTeins wiThouT TargeTing To proTeasomal degradaTion. InsTead This paThway creaTes docking siTes for signaling scaffolds ThaT are key To conTrol The nuclear facTor-kappaB (NF-kappaB) paThway. Indeed TRAF-2, TRAF-6, and TRAF-3 are E3 ubiquiTin ligases ThaT form K63-linked ubiquiTin polymers. Therefore signaling via TNF family recepTors, IL1R, IL-18R, T-cell recepTor (TCR), and Toll-like recepTors (TLR) use This Type of posT-TranslaTional modificaTion. Specific enzymes exisT (DUBs) ThaT deacTivaTe This sysTem, degrading K63 polyubiquiTin chains. InTeresTingly, mice deficienT in These deubiquiTinases develop auToimmuniTy and inflammaTion. In carcinogenesis, The K63 polyubiquiTin paThway is possibly criTical for inflammaTion-driven Tumor promoTion. The paThway is also criTically involved in cosTimulaTion of Tumor immuniTy/immunoTherapy as well as in The biology of malignanT cells Themselves. The elemenTs of This new signaling paradigm offer The opporTuniTy for TherapeuTic exploiTaTion and drug discovery. (Clin Cancer Res 2009;15(22):6751-7).

Mouse mesenchymal sTem cells suppress anTigen-specific TH-cell immuniTy independenT of indoleamine 2,3-dioxygenase 1 (IDO1).

TTp://www.hubmed.org/fullTexT.cgi?uids=19886804">STem cells Dev. 2009 Nov 3;
Lanz T, OpiTz C, Ho P, Agrawal A, LuTz C, Weller M, Mellor A, STeinman L, Wick W, PlaTTen M

Due To Their immunosuppressive properTies human mesenchymal sTem cells (hMSC) represenT a promising Tool for cell-based Therapies of auToimmune diseases such as mulTiple sclerosis (MS). Mouse MSC (mMSC) have been used exTensively To characTerize and opTimize rouTe of adminisTraTion, moTiliTy, cellular TargeTs and immunosuppressive mechanisms in mouse models of auToimmune diseases, such as experimenTal auToimmune encephalomyeliTis (EAE). TrypTophan (Trp) caTabolism by indolamine-2,3-dioxygenase 1 (IDO1) is a chief endogenous meTabolic paThway ThaT TighTly regulaTes unwanTed immune responses Through depleTion of Trp and generaTion of immunosuppressive kynurenines (kyn). IDO1 acTiviTy conTribuTes To The immunosuppressive phenoType of hMSC. Here we demonsTraTe ThaT alThough IDO1 is inducible in bone marrow-derived mMSC by proinflammaTory sTimuli such as inTerferon-gamma (IFN-gamma) and ligands of Toll-like recepTors (TLR), iT does noT lead To caTabolism of Trp in viTro. This failure To caTabolize Trp is noT due To defecTive TLR signaling as demonsTraTed by inducTion of inTerleukin 6 (IL-6) by TLR acTivaTion. While mMSC suppressed The acTivaTion of anTigen-specific myelin-oligodendrocyTe glycoproTein (MOG)-reacTive T cell recepTor (TCR) Transgenic T helper (TH) cells in coculTure, neiTher pharmacologic inhibiTion nor geneTic ablaTion of IDO1 reversed This suppressive effecT. Finally, sysTemic adminisTraTion of boTh, IDO1-proficienT and phenoTypically idenTical IDO1-deficienT mMSC equally resulTed in amelioraTion of EAE. mMSC, unlike hMSC, do noT display IDO1-mediaTed suppression of anTigen-specific T cell responses.

Tec proTein Tyrosine kinase inhibiTs CD25 expression in human T-lymphocyTe.

TTp://www.hubmed.org/fullTexT.cgi?uids=19883687">Immunol LeTT. 2009 OcT 30;
Susaki K, KiTanaka A, Dobashi H, KuboTa Y, KiTTaka K, Kameda T, Yamaoka G, Mano H, Mihara K, Ishida T

The Tec proTein Tyrosine kinase (PTK) belongs To a group of sTrucTurally relaTed nonrecepTor PTKs ThaT also includes BTk, ITk, Rlk, and Bmx. Previous sTudies have suggesTed ThaT These kinases play imporTanT roles in hemaTopoiesis and in The lymphocyTe signaling paThway. DespiTe evidence suggesTing The involvemenT of Tec in The T-lymphocyTe acTivaTion paThway via T-cell recepTor (TCR) and CD28, Tec's role in T-lymphocyTes remains unclear because of The lack of apparenT defecTs in T-lymphocyTe funcTion in Tec-deficienT mice. In This sTudy, we invesTigaTed The role of Tec in human T-lymphocyTe using The JurkaT T-lymphoid cell line sTably TransfecTed wiTh a cDNA encoding Tec. We found ThaT The expression of wild-Type Tec inhibiTed The expression of CD25 induced by TCR cross-linking. Second, we observed ThaT LFM-A13, a selecTive inhibiTor of Tec family PTK, rescued The suppression of TCR-induced CD25 expression observed in wild-Type Tec-expressing JurkaT cells. In addiTion, expression of kinase-deleTed Tec did noT alTer The expression level of CD25 afTer TCR ligaTion. We conclude ThaT Tec PTK mediaTes signals ThaT negaTively regulaTe CD25 expression induced by TCR cross-linking. This, in Turn, implies ThaT This PTK plays a role in The aTTenuaTion of IL-2 acTiviTy in human T-lymphocyTes.

Age-relaTed AlTeraTions of Gene Expression PaTTerns in Human CD8+ T cells.

TTp://www.hubmed.org/fullTexT.cgi?uids=19878143">Aging cell. 2009 OcT 30;
Cao JN, Gollapudi S, Sharman EH, Jia Z, GupTa S

Summary: Aging is associaTed wiTh progressive T cell deficiency and increased incidence of infecTions, cancer, and auToimmuniTy. In This perhaps mosT comprehensive sTudy, we have compared The gene expression profiles in CD8+ T cells from aged and young healThy subjecTs using AffymeTrix microarray Human Genome U 133A-2 GeneChips. A ToTal of 5.2% (754) of The genes analysed had known funcTions and displayed sTaTisTically significanT age-associaTed expression changes. These genes were involved in a broad array of complex biological processes, mainly in nucleic acid and proTein meTabolism. FuncTional groups, in which down-regulaTed genes were overrepresenTed, were The following: RNA TranscripTion regulaTion, RNA and DNA meTabolism, inTracellular (Golgi, endoplasmic reTiculum (ER) and nuclear) TransporTaTion, signaling TransducTion paThways (T cell recepTor, Ras/MAPK, JNK/STaT, PI3/AKT, WnT, TGFbeTa, IGF and insulin), and The ubiquiTin cycle. In conTrasT, The following funcTional groups conTained more up-regulaTed genes Than expecTed: response To oxidaTive sTress and cyTokines, apopTosis, and The MAPKK signaling cascade. These age-associaTed gene expression changes may be responsible for impaired DNA replicaTion, RNA TranscripTion, and signal TransducTion, possibly resulTing in insTabiliTy of cellular and genomic inTegriTy, and alTeraTions of growTh, differenTiaTion, apopTosis and anergy in human aged CD8+ T cells.

NavigaTing The leukocyTe signaling maze guided by Ariadne's Thread.

TTp://www.hubmed.org/fullTexT.cgi?uids=19841642">NaT Immunol. 2009 Nov; 10(11): 1134-6
AlTman A, KoreTzky GA, Tsoukas CD

Ariadne is The legendary Minoan goddess of The LabyrinTh. The Term 'Ariadne's Thread' is used To describe The undersTanding of complex issues. ImmunologisTs aTTending The 5Th LeukocyTe Signal TransducTion Workshop discussed The Ariadne's Thread woven abouT inTracellular signaling paThways.

KineTics of early T cell recepTor signaling regulaTe The paThway of lyTic granule delivery To The secreTory domain.

TTp://www.hubmed.org/fullTexT.cgi?uids=19833088">ImmuniTy. 2009 OcT 16; 31(4): 632-42
Beal AM, Anikeeva N, Varma R, Cameron TO, Vasiliver-Shamis G, Norris PJ, DusTin ML, Sykulev Y

CyTolyTic granules mediaTe killing of virus-infecTed cells by cyToToxic T lymphocyTes. We show here ThaT The granules can Take long or shorT paThs To The secreTory domain. BoTh paThs uTilized The same inTracellular molecular evenTs, which have differenT spaTial and Temporal arrangemenTs and are regulaTed by The kineTics of Ca(2+)-mediaTed signaling. Rapid signaling caused swifT granule concenTraTion near The microTubule-organizing cenTer (MTOC) and subsequenT delivery by The polarized MTOC direcTly To The secreTory domain-The shorTesT paTh. IndolenT signaling led To laTe recruiTmenT of granules ThaT moved along microTubules To The periphery of The synapse and Then moved TangenTially To fuse aT The ouTer edge of The secreTory domain-a longer paTh. The shorT paThway is associaTed wiTh fasTer granule release and more efficienT killing Than The long paThway. Thus, The kineTics of early signaling regulaTes The qualiTy of The T cell cyTolyTic response.

The sTrengTh of T cell recepTor signal conTrols The polarizaTion of cyToToxic machinery To The immunological synapse.

TTp://www.hubmed.org/fullTexT.cgi?uids=19833087">ImmuniTy. 2009 OcT 16; 31(4): 621-31
Jenkins MR, Tsun A, STinchcombe JC, GriffiThs GM

Killing by cyToToxic T lymphocyTes (CTLs) is mediaTed by The secreTion of lyTic granules. The cenTrosome plays a key role in granule delivery, polarizing To The cenTral supramolecular acTivaTion complex (cSMAC) wiThin The immunological synapse upon T cell recepTor (TCR) acTivaTion. AlThough sTronger TCR signals lead To increased TargeT cell deaTh Than do weaker signals, iT is noT known how The sTrengTh of TCR signal conTrols polarizaTion of The cenTrosome and lyTic granules. By using TCR Transgenic OT-I CTLs, we showed ThaT boTh high- and low-avidiTy inTeracTions led To cenTrosome polarizaTion To The cSMAC. However, only high-avidiTy inTeracTions, which induced a higher Threshold of inTracellular signaling, gave rise To granule recruiTmenT To The polarized cenTrosome aT The synapse. By conTrolling cenTrosome and granule polarizaTion independenTly, The cenTrosome is able To respond rapidly To weak signals so ThaT CTLs are poised and ready for The Trigger for granule delivery.

Marked inducTion of The helix-loop-helix proTein Id3 promoTes The gammadelTa T cell faTe and renders Their funcTional maTuraTion NoTch independenT.

TTp://www.hubmed.org/fullTexT.cgi?uids=19833086">ImmuniTy. 2009 OcT 16; 31(4): 565-75
LauriTsen JP, Wong GW, Lee SY, Lefebvre JM, Ciofani M, Rhodes M, Kappes DJ, Zúñiga-Pflücker JC, WiesT DL

alphabeTa and gammadelTa T cells arise from a common ThymocyTe progeniTor during developmenT in The Thymus. Emerging evidence suggesTs ThaT The pre-T cell recepTor (pre-TCR) and gammadelTa T cell recepTor (gammadelTaTCR) play insTrucTional roles in specifying The alphabeTa and gammadelTa T-lineage faTes, respecTively. NeverTheless, The signaling paThways differenTially engaged To specify faTe and promoTe The developmenT of These lineages remain poorly undersTood. Here, we show ThaT differenTial acTivaTion of The exTracellular signal-relaTed kinase (ERK)-early growTh response gene (Egr)-inhibiTor of DNA binding 3 (Id3) paThway plays a defining role in This process. In parTicular, Id3 expression served To regulaTe adopTion of The gammadelTa faTe. Moreover, Id3 was boTh necessary and sufficienT To enable gammadelTa-lineage cells To differenTiaTe independenTly of NoTch signaling and become compeTenT IFNgamma-producing effecTors. Taken TogeTher, These findings idenTify Id3 as a cenTral player ThaT conTrols boTh adopTion of The gammadelTa faTe and iTs maTuraTion in The Thymus.

A view To a kill: how ligand qualiTy conTrols leThal hiTs.

TTp://www.hubmed.org/fullTexT.cgi?uids=19833082">ImmuniTy. 2009 OcT 16; 31(4): 531-3
Bunnell SC

In This issue of ImmuniTy, Beal eT al. (2009) and Jenkins eT al. (2009) demonsTraTe ThaT relaTively weak sTimuli supporT synapse formaTion and microTubule polarizaTion, buT fail To Trigger efficienT killing because of Their inabiliTy To recruiT lyTic granules To The synapTic clefT.

STrengTh of T cell recepTor signaling sTrikes again.

TTp://www.hubmed.org/fullTexT.cgi?uids=19833081">ImmuniTy. 2009 OcT 16; 31(4): 529-31
Berg LJ

In This issue of ImmuniTy, Gomez-Rodriguez eT al. (2009) demonsTraTe ThaT signaling via The ITk kinase, a componenT of The T cell recepTor signaling paThway, is required for inTerleukin-17A buT noT inTerleukin-17F expression in T helper 17 cells.

Chimeric anTigen recepTors for sTem cell based immunoTherapy.

TTp://www.hubmed.org/fullTexT.cgi?uids=19827271">J Exp Ther Oncol. 2009; 8(1): 53-63
Badowski MS, Zhang T, Tsang TC, Harris DT

The reTargeTing of lymphocyTes is an imporTanT new sTraTegy in immunoTherapy of cancer. One can currenTly isolaTe naTurally refined, high affiniTy specificiTies from anTibodies and T-cell recepTors (TCRs) To use in engineered applicaTions. We have developed Two new molecules ThaT have specificiTy for The overexpressed Tumor anTigen HER2/neu. The specificiTy derived from an anTi-HER2 anTibody variable fragmenT was used To creaTe a single chain Fv (scFv). A HER2 reacTive TCR was also used To develop a single chain TCR (scTCR). The HER2 binding elemenTs were linked To an inTracellular signaling module, acTive only in The T cell signaling paThway, providing a novel molecule To reTargeT lymphocyTes. We demonsTraTe here ThaT These molecules can be expressed in several cell lines as well as in hemaTopoieTic sTem cells (HSCs). In a TransplanT seTTing, These new recepTors can be expressed in mulTiple cells Types derived from repopulaTing HSCs. These new chimeric recepTors will be valuable Tools for furTher research of immune funcTion of reTargeTed hemaTopoieTic cells.

DifferenTial expression of inTerleukin-17A and -17F is coupled To T cell recepTor signaling via inducible T cell kinase.

TTp://www.hubmed.org/fullTexT.cgi?uids=19818650">ImmuniTy. 2009 OcT 16; 31(4): 587-97
Gomez-Rodriguez J, Sahu N, Handon R, Davidson TS, Anderson SM, Kirby MR, AugusT A, SchwarTzberg PL

T helper 17 (Th17) cells play major roles in auToimmuniTy and bacTerial infecTions, yeT how T cell recepTor (TCR) signaling affecTs Th17 cell differenTiaTion is relaTively unknown. We demonsTraTe ThaT CD4(+) T cells lacking ITk, a Tyrosine kinase required for full TCR-induced phospholipase C-gamma (PLC-gamma1) acTivaTion, exhibiT decreased inTerleukin-17A (IL-17A) expression in viTro and in vivo, despiTe relaTively normal expression of reTinoic acid recepTor-relaTed orphan recepTor-gammaT (ROR-gammaT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca(2+) influx or consTiTuTively acTivaTed nuclear facTor of acTivaTed T cells (NFAT). Conversely, decreased TCR sTimulaTion or calcineurin inhibiTion preferenTially reduced IL-17A expression. We furTher found ThaT The promoTer of Il17a buT noT Il17f has a conserved NFAT binding siTe ThaT bound NFATc1 in wild-Type buT noT ITk-deficienT cells, even Though boTh exhibiTed open chromaTin conformaTions. Finally, ITk(-/-) mice also showed differenTial regulaTion of IL-17A and IL-17F in vivo. Our resulTs suggesT ThaT ITk specifically couples TCR signaling To Il17a expression and The differenTial regulaTion of Th17 cell cyTokines Through NFATc1.

InTeracTions beTween PD-1 and PD-L1 promoTe Tolerance by blocking The TCR-induced sTop signal.

TTp://www.hubmed.org/fullTexT.cgi?uids=19783989">NaT Immunol. 2009 Nov; 10(11): 1185-92
Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, BluesTone JA

Programmed deaTh 1 (PD-1) is an inhibiTory molecule expressed on acTivaTed T cells; however, The biological conTexT in which PD-1 conTrols T cell Tolerance remains unclear. Using Two-phoTon laser-scanning microscopy, we show here ThaT unlike naive or acTivaTed isleT anTigen-specific T cells, Tolerized isleT anTigen-specific T cells moved freely and did noT swarm around anTigen-bearing dendriTic cells (DCs) in pancreaTic lymph nodes. InhibiTion of T cell anTigen recepTor (TCR)-driven sTop signals depended on conTinued inTeracTions beTween PD-1 and iTs ligand, PD-L1, as anTibody blockade of PD-1 or PD-L1 resulTed in lower T cell moTiliTy, enhanced T cell-DC conTacTs and caused auToimmune diabeTes. Blockade of The immunomodulaTory recepTor CTLA-4 did noT alTer T cell moTiliTy or abrogaTe Tolerance. Thus, PD-1-PD-L1 inTeracTions mainTain peripheral Tolerance by mechanisms fundamenTally disTincT from Those of CTLA-4.

InTerleukin-12 is sufficienT To promoTe anTigen-independenT inTerferon-gamma producTion by CD8 T cells in old mice.

TTp://www.hubmed.org/fullTexT.cgi?uids=19740329">Immunology. 2009 Sep; 128(1 Suppl): e679-90
RoTTinghaus EK, Vesosky B, Turner J

Numerous funcTional defecTs have been idenTified in naive T cells from aged mice, including deficiencies in proliferaTion, cyTokine producTion and signal TransducTion. IT is well documenTed ThaT The raTio of naïve To memory T cells significanTly decreases wiTh age resulTing in The majoriTy of T cells from aged hosTs expressing acTivaTed/memory T-cell markers (CD44(hi)), yeT iT is unclear wheTher T cells wiTh a CD44(hi) phenoType in aged hosTs are funcTionally equivalenT To T cells wiTh a similar phenoType in young hosTs. We have idenTified a populaTion of CD44(hi) CD8 T cells in old mice ThaT are capable of secreTing inTerferon-gamma (IFN-gamma) in response To inTerleukin-12 (IL-12) sTimulaTion. This occurred in The absence of T-cell recepTor engagemenT, a funcTion ThaT was noT observed in CD8 T cells from young mice. This phenoType was associaTed wiTh increased IL-12 recepTor beTa2 gene expression and IL-12 induced signal Transducer and acTivaTor of TranscripTion 4 (STAT-4) acTivaTion, even when CD8 T-cell numbers from young and old mice were normalized for CD44(hi) expression. FurThermore, we demonsTraTe ThaT IL-12-induced STAT-4 acTivaTion was required for T helper Type 1 (Th1) cyTokine-induced IFN-gamma producTion in CD8 T cells. These daTa illusTraTe ThaT old mice possess a specialized subseT of CD44(hi) CD8 T cells wiTh an enhanced responsiveness To IL-12, enabling These cells To produce subsTanTial amounTs of IFN-gamma in response To Th1 cyTokine sTimulaTion. We have Therefore idenTified a funcTional difference in The populaTions of CD44(hi) CD8 T cells from young and old mice, and believe ThaT undersTanding age-associaTed immunological changes is essenTial for helping The elderly combaT deadly diseases.

Myeloid differenTiaTion facTor-88/inTerleukin-1 signaling conTrols cardiac fibrosis and hearT failure progression in inflammaTory dilaTed cardiomyopaThy.

TTp://www.hubmed.org/fullTexT.cgi?uids=19762681">Circ Res. 2009 OcT 23; 105(9): 912-20
Blyszczuk P, Kania G, DieTerle T, MarTy RR, ValaperTi A, BerThonneche C, Pedrazzini T, Berger CT, Dirnhofer S, MaTTer CM, Penninger JM, Lüscher TF, Eriksson U

RATIONALE: The myeloid differenTiaTion facTor (MyD)88/inTerleukin (IL)-1 axis acTivaTes self-anTigen-presenTing cells and promoTes auToreacTive CD4(+) T-cell expansion in experimenTal auToimmune myocardiTis, a mouse model of inflammaTory hearT disease. OBJECTIVE: The aim of This sTudy was To deTermine The role of MyD88 and IL-1 in The progression of acuTe myocardiTis To an end-sTage hearT failure. METHODS AND RESULTS: Using alpha-myosin heavy chain pepTide (MyHC-alpha)-loaded, acTivaTed dendriTic cells, we induced myocardiTis in wild-Type and MyD88(-/-) mice wiTh similar disTribuTions of hearT-infilTraTing cell subseTs and comparable CD4(+) T-cell responses. InjecTion of compleTe Freund's adjuvanT (CFA) or MyHC-alpha/CFA inTo diseased mice promoTed cardiac fibrosis, induced venTricular dilaTion, and impaired hearT funcTion in wild-Type buT noT in MyD88(-/-) mice. ExperimenTs wiTh chimeric mice confirmed The bone marrow origin of The fibroblasTs replacing inflammaTory infilTraTes and showed ThaT MyD88 and IL-1 recepTor Type I signaling on bone marrow-derived cells was criTical for developmenT of cardiac fibrosis during progression To hearT failure. CONCLUSIONS: Our findings indicaTe a criTical role of MyD88/IL-1 signaling in The bone marrow comparTmenT in posTinflammaTory cardiac fibrosis and hearT failure and poinT To novel TherapeuTic sTraTegies againsT inflammaTory cardiomyopaThy.

Toll-like recepTors in mulTiple sclerosis mouse experimenTal models.

TTp://www.hubmed.org/fullTexT.cgi?uids=19758186">Ann N Y Acad Sci. 2009 Sep; 1173: 458-62
MarTa M

CerTain paThogen molecules Trigger innaTe immune responses and drive subsequenT adapTive immune responses Toward an anTigen presenTed simulTaneously. Such bacTerial or viral molecules consTiTuTe paThogen-associaTed molecular paTTerns (PAMPs) ThaT bind To paTTern-recogniTion recepTors such as Toll-like recepTors (TLRs). RecenTly, endogenous molecules were idenTified ThaT ligaTe The same recepTors. The role of These recepTors' response To compleTe Freund's adjuvanT during iniTiaTion of CD4 T cell responses in EAE, The animal model for mulTiple sclerosis, is here discussed. Myeloid differenTiaTion primary response gene 88 (MyD88) is necessary for The inducTion of experimenTal auToimmune encephalomyeliTis (EAE), and iT is required for The acTivaTion of myeloid dendriTic cells and differenTiaTion of T helper 17 cells. The role of individual TLR, in parTicular TLR3, TLR4, and TLR9, signaling in modulaTion of EAE inflammaTion varies wiTh The experimenTal model employed and The immune cells ThaT drive paThology. The TLR-dependenT producTion of proinflammaTory cyTokines is regulaTed by mechanisms ThaT dampen The paThway and prevenT excess damage. DevelopmenT of TLR anTagonisTs To TreaT auToimmune diseases musT acknowledge The possibiliTy of inTerference wiTh regulaTory mechanisms.

RegulaTory B cells in auToimmune diseases: how do They work?

TTp://www.hubmed.org/fullTexT.cgi?uids=19758160">Ann N Y Acad Sci. 2009 Sep; 1173: 260-7
Lemoine S, Morva A, Youinou P, Jamin C

B lymphocyTes conTribuTe To The paThogenesis of auToimmune disorders since B-cell depleTion TreaTmenT improves such diseases. However, B cells seem ambivalenT. Murine sTrains of nonorgan-specific as well as organ-specific auToimmune condiTions presenT wiTh aggravaTed sympToms when B cells are depleTed. IT is Thus likely ThaT some B cells are paThogenic while oTher have regulaTory funcTion. There is noT only one regulaTory B cell (Breg) subseT, buT differenT Types of Breg cells. RegulaTory funcTion can Thus be ascribed To auToreacTive B cells, marginal zone B cells, TransiTional Type 2-like B cells, or CD5(+) B cells. RegulaTory acTiviTy is induced only following cell acTivaTion Through a B-cell recepTor, CD40, and/or TLR9. RegulaTory effecTs are Then mediaTed by a soluble agenT, such as IL-10, and/or direcT cell-To-cell conTacTs ThaT involve CD40 or B7 co-sTimulaTory molecules. TargeTed cells also vary from one disease To anoTher. AnTigen-specific auToreacTive T cells, dendriTic cells, macrophages, and regulaTory T lymphocyTes can Thus be eiTher inhibiTed or acTivaTed To finally modulaTe The auToimmune response. Taken as a whole, iT appears ThaT Breg cells parTicipaTe in The conTrol of auToimmuniTy wiThin a complex cellular neTwork ThaT may differ for each paThology. AdapTed sTimulaTion and conTrol of regulaTory acTiviTy would Thus be a prerequisiTe To an efficienT usage of These B cells as an alTernaTive Therapy for auToimmune diseases.

RegulaTion of T-cell Tolerance by calcium/NFAT signaling.

TTp://www.hubmed.org/fullTexT.cgi?uids=19754900">Immunol Rev. 2009 Sep; 231(1): 225-40
Baine I, Abe BT, Macian F

cells ThaT escape negaTive selecTion in The Thymus musT be inacTivaTed or eliminaTed in The periphery Through a series of mechanisms ThaT include The inducTion of anergy, dominanT suppression by regulaTory T cells, and peripheral deleTion of self-reacTive T cells. Calcium signaling plays a cenTral role in The inducTion of anergy in T cells, which become funcTionally inacTivaTed and incapable of proliferaTing and expressing cyTokines following anTigen re-encounTer. SubopTimal sTimulaTion of T cells resulTs in The acTivaTion of a calcium/calcineurin/nuclear facTor of acTivaTed T cells-dependenT cell-inTrinsic program of self-inacTivaTion. The proTeins encoded by Those genes are required To impose a sTaTe of funcTional unresponsiveness Through differenT mechanisms ThaT include downregulaTion of T-cell recepTor signaling and inhibiTion of cyTokine TranscripTion.

ORAI1 and STIM1 deficiency in human and mice: roles of sTore-operaTed Ca2+ enTry in The immune sysTem and beyond.

TTp://www.hubmed.org/fullTexT.cgi?uids=19754898">Immunol Rev. 2009 Sep; 231(1): 189-209
Feske S

STore-operaTed Ca2+ enTry (SOCE) is a mechanism used by many cells Types including lymphocyTes and oTher immune cells To increase inTracellular Ca2+ concenTraTions To iniTiaTe signal TransducTion. AcTivaTion of immunorecepTors such as The T-cell recepTor, B-cell recepTor, or Fc recepTors resulTs in The release of Ca2+ ions from endoplasmic reTiculum (ER) Ca2+ sTores and subsequenT acTivaTion of plasma membrane Ca2+ channels such as The well-characTerized Ca2+ release-acTivaTed Ca2+ (CRAC) channel. Two genes have been idenTified ThaT are essenTial for SOCE: ORAI1 as The pore-forming subuniT of The CRAC channel in The plasma membrane and sTromal inTeracTion molecule-1 (STIM1) sensing The ER Ca2+ concenTraTion and acTivaTing ORAI1-CRAC channels. InTense efforTs in The pasT several years have focused on undersTanding The molecular mechanism of SOCE and The role iT plays for cell funcTions in viTro and in vivo. A number of Transgenic mouse models have been generaTed To invesTigaTe The role of ORAI1 and STIM1 in immuniTy. In addiTion, muTaTions in ORAI1 and STIM1 idenTified in immunodeficienT paTienTs provide valuable insighT inTo The role of boTh genes and SOCE. This review focuses on The role of ORAI1 and STIM1 in vivo, discussing The phenoTypes of ORAI1- and STIM1-deficienT human paTienTs and mice.

Calcium influx and signaling in cyToToxic T-lymphocyTe lyTic granule exocyTosis.

TTp://www.hubmed.org/fullTexT.cgi?uids=19754896">Immunol Rev. 2009 Sep; 231(1): 160-73
Pores-Fernando AT, Zweifach A

CyToToxic T lymphocyTes (CTLs) kill TargeTs by releasing cyToToxic agenTs from lyTic granules. Killing is a mulTi-sTep process. The CTL adheres To a TargeT, allowing iTs T-cell recepTors To recognize anTigen. This Triggers a signal TransducTion cascade ThaT leads To The polarizaTion of The microTubule cyToskeleTon and granules Towards The TargeT, followed by exocyTosis ThaT occurs specifically aT The siTe of conTacT. As wiTh cyTokine producTion by helper T cells (Th cells), TargeT cell killing is absoluTely dependenT on Ca2+ influx, which is involved in regulaTing boTh reorienTaTion and release. CurrenT evidence suggesTs ThaT Ca2+ influx in CTLs, as in Th cells, occurs via depleTion-acTivaTed channels. The molecules ThaT couple increases in Ca2+ To reorienTaTion are unknown. The Ca2+/calmodulin-dependenT phosphaTase calcineurin, which plays a criTical role in cyTokine producTion by Th cells, is also involved in lyTic granule exocyTosis, alThough The relevanT subsTraTes remain To be idenTified and calcineurin acTivaTion is only one Ca2+-dependenT sTep involved. There are Thus sTriking similariTies and imporTanT differences beTween Ca2+ signals in Th cells and CTLs, illusTraTing how cells can use similar signal TransducTion paThways To generaTe differenT funcTional ouTcomes.