Kegg Pathway: T cell receptor signaling pathway

TTp://www.hubmed.org/fullTexT.cgi?uids=19567830">Proc NaTl Acad Sci U S A. 2009 Jun 30;
Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, Fairchild PJ, Mellor AL, Ron D, Waldmann H

InfecTious Tolerance describes The process of CD4(+) regulaTory T cells (Tregs) converTing naïve T cells To become addiTional Tregs. We show ThaT anTigen-specific Tregs induce, wiThin skin grafTs and dendriTic cells, The expression of enzymes ThaT consume aT leasT 5 differenT essenTial amino acids (EAAs). T cells fail To proliferaTe in response To anTigen when any 1, or more, of These EAAs are limiTing, which is associaTed wiTh a reduced mammalian TargeT of rapamycin (mTOR) signaling. InhibiTion of The mTOR paThway by limiTing EAAs, or by specific inhibiTors, induces The Treg-specific TranscripTion facTor forkhead box P3, which depends on boTh T cell recepTor acTivaTion and synergy wiTh TGF-beTa.

TTp://www.hubmed.org/fullTexT.cgi?uids=19541638">Proc NaTl Acad Sci U S A. 2009 Jun 30; 106(26): 10678-83
Dammermann W, Zhang B, Nebel M, Cordiglieri C, Odoardi F, Kirchberger T, Kawakami N, Dowden J, Schmid F, Dornmair K, Hohenegger M, Flügel A, Guse AH, PoTTer BV

The nucleoTide NAADP was recenTly discovered as a second messenger involved in The iniTiaTion and propagaTion of Ca(2+) signaling in lymphoma T cells, buT iTs impacT on primary T cell funcTion is sTill unknown. An opTimized, synTheTic, small molecule inhibiTor of NAADP acTion, Termed BZ194, was designed and synThesized. BZ194 neiTher inTerfered wiTh Ca(2+) mobilizaTion by d-myo-inosiTol 1,4,5-TrisphosphaTe or cyclic ADP-ribose nor wiTh capaciTaTive Ca(2+) enTry. BZ194 specifically and effecTively blocked NAADP-sTimulaTed [(3)H]ryanodine binding To The purified Type 1 ryanodine recepTor. FurTher, in inTacT T cells, Ca(2+) mobilizaTion evoked by NAADP or by formaTion of The immunological synapse beTween primary effecTor T cells and asTrocyTes was inhibiTed by BZ194. DownsTream evenTs of Ca(2+) mobilizaTion, such as nuclear TranslocaTion of "nuclear facTor of acTivaTed T cells" (NFAT), T cell recepTor-driven inTerleukin-2 producTion, and proliferaTion in anTigen-experienced CD4(+) effecTor T cells, were aTTenuaTed by The NAADP anTagonisT. Taken TogeTher, specific inhibiTion of The NAADP signaling paThway consTiTuTes a way To specifically and effecTively modulaTe T-cell acTivaTion and has poTenTial in The Therapy of auToimmune diseases.

TTp://www.hubmed.org/fullTexT.cgi?uids=19525933">NaTure. 2009 Jun 14;
Zanoni I, OsTuni R, Capuano G, Collini M, Caccia M, Ronchi AE, RoccheTTi M, Mingozzi F, FoTi M, Chirico G, CosTa B, Zaza A, Ricciardi-CasTagnoli P, Granucci F

Toll-like recepTors (TLRs) are The besT characTerized paTTern recogniTion recepTors. Individual TLRs recruiT diverse combinaTions of adapTor proTeins, Triggering signal TransducTion paThways and leading To The acTivaTion of various TranscripTion facTors, including nuclear facTor kappaB, acTivaTion proTein 1 and inTerferon regulaTory facTors. InTerleukin-2 is one of The molecules produced by mouse dendriTic cells afTer sTimulaTion by differenT paTTern recogniTion recepTor agonisTs. By analogy wiTh The evenTs afTer T-cell recepTor engagemenT leading To inTerleukin-2 producTion, iT is Therefore plausible ThaT The sTimulaTion of TLRs on dendriTic cells may lead To acTivaTion of The Ca(2+)/calcineurin and NFAT (nuclear facTor of acTivaTed T cells) paThway. Here we show ThaT mouse dendriTic cell sTimulaTion wiTh lipopolysaccharide (LPS) induces Src-family kinase and phospholipase Cgamma2 acTivaTion, influx of exTracellular Ca(2+) and calcineurin-dependenT nuclear NFAT TranslocaTion. The iniTiaTion of This paThway is independenT of TLR4 engagemenT, and dependenT exclusively on CD14. We also show ThaT LPS-induced NFAT acTivaTion via CD14 is necessary To cause The apopToTic deaTh of Terminally differenTiaTed dendriTic cells, an evenT ThaT is essenTial for mainTaining self-Tolerance and prevenTing auToimmuniTy. ConsequenTly, blocking This paThway in vivo causes prolonged dendriTic cell survival and an increase in T-cell priming capabiliTy. Our findings reveal novel aspecTs of molecular signalling Triggered by LPS in dendriTic cells, and idenTify a new role for CD14: The regulaTion of The dendriTic cell life cycle Through NFAT acTivaTion. Given The involvemenT of CD14 in disease, including sepsis and chronic hearT failure, The discovery of signal TransducTion paThways acTivaTed exclusively via CD14 is an imporTanT sTep Towards The developmenT of poTenTial TreaTmenTs involving inTerference wiTh CD14 funcTions.

TTp://www.hubmed.org/fullTexT.cgi?uids=19494338">J Immunol. 2009 Jun 15; 182(12): 8118-24
Li J, Herold MJ, Kimmel B, Müller I, Rincon-Orozco B, Kunzmann V, Herrmann T

Human Vgamma9VdelTa2 T cells are characTerized by a unique specificiTy for cerTain Tumors (e.g., Daudi), cells presenTing so-called phosphoanTigens such as isopenTenyl pyrophosphaTe (IPP), or cells TreaTed wiTh aminobisphosphonaTes. We now reporT conversion of hemaTopoieTic and nonhemaTopoieTic Tumor cell lines inTo Vgamma9VdelTa2 T cell acTivaTors by means of shorT hairpin RNA-mediaTed knockdown of expression of The IPP-consuming enzyme, farnesyl pyrophosphaTe synThase (FPPS). FPPS knockdown cells acTivaTed Vgamma9VdelTa2 T cells, as measured by increased levels of CD69 and CD107a, killing of FPPS knockdown cells, and inducTion of IFN-gamma secreTion. The IPP-synThesis-inhibiTing drug mevasTaTin reduced Vgamma9VdelTa2 T cell acTivaTion by FPPS knockdown cells buT noT acTivaTion by The phosphoanTigen bromohydrin pyrophosphaTe. In conclusion, our daTa supporT The concepT of Vgamma9VdelTa2 T cells as sensors of a dysregulaTed isoprenoid meTabolism and suggesT TherapeuTic down-modulaTion of FPPS expression as an addiTional Tool To TargeT Tumor cells To Vgamma9VdelTa2 T cell-mediaTed immunosurveillance.

TTp://www.hubmed.org/fullTexT.cgi?uids=19494296">J Immunol. 2009 Jun 15; 182(12): 7718-28
Düwel M, WelTeke V, Oeckinghaus A, Baens M, Kloo B, Ferch U, Darnay BG, Ruland J, Marynen P, Krappmann D

The Carma1-Bcl10-MalT1 signaling module bridges TCR signaling To The canonical IkappaB kinase (IKK)/NF-kappaB paThway. CovalenT aTTachmenT of regulaTory ubiquiTin chains To MalT1 paracaspase direcTs TCR signaling To IKK acTivaTion. FurTher, The ubiquiTin-ediTing enzyme A20 was recenTly suggesTed To suppress T cell acTivaTion, buT molecular TargeTs for A20 remain elusive. In This paper, we show ThaT A20 regulaTes The sTrengTh and duraTion of The IKK/NF-kappaB response upon TCR/CD28 cosTimulaTion. By caTalyzing The removal of K63-linked ubiquiTin chains from MalT1, A20 prevenTs susTained inTeracTion beTween ubiquiTinaTed MalT1 and The IKK complex and Thus serves as a negaTive regulaTor of inducible IKK acTiviTy. Upon T cell sTimulaTion, A20 is rapidly removed and paracaspase acTiviTy of MalT1 has been suggesTed To cleave A20. Using anTagonisTic pepTides or reconsTiTuTion of MalT1(-/-) T cells, we show ThaT MalT1 paracaspase acTiviTy is required for A20 cleavage and opTimal IL-2 producTion, buT dispensable for iniTial IKK/NF-kappaB signaling in CD4(+) T cells. However, proTeasomal inhibiTion impairs A20 degradaTion and impedes TCR/CD28-induced IKK acTivaTion. Taken TogeTher, A20 funcTions as a MalT1 deubiquiTinaTing enzyme and proTeasomal degradaTion and de novo synThesis of A20 conTribuTes To balance TCR/CD28-induced IKK/NF-kappaB signaling.

TTp://www.hubmed.org/fullTexT.cgi?uids=19494292">J Immunol. 2009 Jun 15; 182(12): 7681-9
Gérard A, GhioTTo M, Fos C, GuiTTard G, Compagno D, Galy A, Lemay S, Olive D, Nunès JA

Dok-4 (downsTream of Tyrosine kinase-4) is a recenTly idenTified member of The Dok family of adapTor proTeins, which are characTerized by an amino-Terminal plecksTrin homology domain, a phosphoTyrosine-binding domain, and a carboxyl-Terminal region conTaining several Tyrosines and poly-proline-rich moTifs. Two members of The Dok family, Dok-1 and Dok-2, have already been described as negaTive regulaTors in T cells. However, The funcTion of Dok-4, which is also expressed in T cells, remains unknown. In This sTudy, we reporT ThaT Dok-4 is phosphorylaTed afTer TCR engagemenT and shuTTled wiThin The cyToplasm of T cells before being recruiTed To The polarized microTubule organizing cenTer afTer The formaTion of The immunological synapse. Loss-of-funcTion experimenTs using RNA inTerference consTrucTs show ThaT Dok-4 is a negaTive regulaTor of ERK phosphorylaTion, IL-2 promoTer acTiviTy, and T cell proliferaTion. Exogenous expression of wild-Type Dok-4 induces a significanT acTivaTion of Rap1, which is involved in The regulaTion of ERK. The plecksTrin homology domain of Dok-4 is required boTh for iTs cyToplasmic shuTTling and relocalizaTion as well as for iTs inhibiTory properTies on T cell acTivaTion. Thus, Dok-4 represenTs a novel negaTive regulaTor of T cells.

TTp://www.hubmed.org/fullTexT.cgi?uids=19494254">J Immunol. 2009 Jun 15; 182(12): 7331-41
Wells AD

The verTebraTe immune sysTem has evolved To deal wiTh invasive paThogens, buT This adapTaTion comes aT The expense of immunopaThology. Among a number of mechanisms ThaT coevolved To conTrol adapTive immuniTy is anergy, The funcTional inacTivaTion of T lymphocyTes ThaT respond To Ag in The absence of inflammaTion. In This review, I highlighT a series of inTracellular proTeins in quiescenT T cells ThaT funcTion To inTegraTe signals from Ag, cosTimulaTory, and growTh facTor recepTors. These facTors ensure ThaT cells ThaT fail To engage all Three paThways are shunTed inTo an alTernaTive TranscripTional program designed To dissuade Them from parTicipaTing in subsequenT immune responses. RecenT sTudies indicaTe ThaT anergy is The combined resulT of facTors ThaT negaTively regulaTe proximal TCR-coupled signal TransducTion, TogeTher wiTh a program of acTive TranscripTional silencing ThaT is reinforced Through epigeneTic mechanisms.

TTp://www.hubmed.org/fullTexT.cgi?uids=19481264">Mol Immunol. 2009 Jul; 46(11-12): 2167-77
Wu L, Bijian K, Shen SS

IT has been exTensively documenTed ThaT CD45 posiTively regulaTes T cell recepTor-mediaTed signaling Through The acTivaTion of Src-family kinases. The mechanism whereby CD45 negaTively regulaTes The JAK/STAT paThway, however, has noT been fully elucidaTed. Here we describe The mechanism by which CD45 negaTively regulaTes The JAK/STAT paThway Through The recruiTmenT of The inhibiTory molecule DownsTream of Kinase 1 (DOK-1) in hemaTopoieTic cells. We presenT evidences ThaT CD45 recruiTs DOK-1 To associaTe wiTh Tyrosine-phosphorylaTed DOK-1, and ThaT The DOK-1-Y296F muTanT compleTely abrogaTes iTs inTeracTion wiTh CD45. Moreover, CD45 expression is required for DOK-1 TargeTing To The plasma membrane in response To anTi-CD3 sTimulaTion. FuncTional sTudies furTher showed ThaT sTable expression of DOK-1 in K562 cells markedly decreased boTh JAK-2 and STAT-3/5 phosphorylaTion following IL-3 and IFN-alpha sTimulaTion. Likewise, sTable expression of DOK-1 in JurkaT cells significanTly decreased JAK-2 phosphorylaTion. Similarly, boTh IL-3 and IFN-alpha-induced JAK-2 phosphorylaTions were significanTly increased in CD45 deficienT JurkaT cells. ConsisTenTly, silencing of The DOK-1 gene resulTed in rescue of MAP kinases and JAKs acTiviTies in CD45 posiTive JurkaT cells. Accordingly, CD45 recruiTs adapTor DOK-1 To The proximal plasma membrane To serve as a downsTream effecTor, resulTing in negaTive regulaTion of The JAK/STAT signaling paThway.

TTp://www.hubmed.org/fullTexT.cgi?uids=19479075">PLoS One. 2009; 4(5): e5657
Correia DV, d'Orey F, Cardoso BA, Lança T, Grosso AR, deBarros A, MarTins LR, BaraTa JT, Silva-SanTos B

BACKGROUND: The unique responsiveness of Vgamma9VdelTa2 T-cells, The major gammadelTa subseT of human peripheral blood, To non-pepTidic prenyl pyrophosphaTe anTigens consTiTuTes The basis of currenT gammadelTa T-cell-based cancer immunoTherapy sTraTegies. However, The molecular mechanisms responsible for phosphoanTigen-mediaTed acTivaTion of human gammadelTa T-cells remain unclear. In parTicular, previous reporTs have described a very slow kineTics of acTivaTion of T-cell recepTor (TCR)-associaTed signal TransducTion paThways by isopenTenyl pyrophosphaTe and bromohydrin pyrophosphaTe, seemingly incompaTible wiTh direcT binding of These anTigens To The Vgamma9VdelTa2 TCR. Here we have sTudied The mosT poTenT naTural phosphoanTigen yeT idenTified, (E)-4-hydroxy-3-meThyl-buT-2-enyl pyrophosphaTe (HMB-PP), produced by EubacTeria and ProTozoa, and examined iTs gammadelTa T-cell acTivaTion and anTi-Tumor properTies. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparaTive sTudy beTween HMB-PP and The anTi-CD3epsilon monoclonal anTibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed mulTiple cellular and molecular gammadelTa T-cell acTivaTion evenTs. We show ThaT HMB-PP acTivaTes MEK/Erk and PI-3K/AkT paThways as rapidly as OKT3, and induces an almosT idenTical TranscripTional profile in Vgamma9(+) T-cells. Moreover, MEK/Erk and PI-3K/AkT acTiviTies are indispensable for The cellular effecTs of HMB-PP, including gammadelTa T-cell acTivaTion, proliferaTion and anTi-Tumor cyToToxiciTy, which are also abolished upon anTibody blockade of The Vgamma9(+) TCR Surprisingly, HMB-PP TreaTmenT does noT induce down-modulaTion of surface TCR levels, and Thereby susTains gammadelTa T-cell acTivaTion upon re-sTimulaTion. This ulTimaTely TranslaTes in poTenT human gammadelTa T-cell anTi-Tumor funcTion boTh in viTro and in vivo upon TransplanTaTion of human leukemia cells inTo lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The developmenT of efficienT cancer immunoTherapy sTraTegies criTically depends on our capaciTy To maximize anTi-Tumor effecTor T-cell responses. By characTerizing The inTracellular mechanisms of HMB-PP-mediaTed acTivaTion of The highly cyToToxic Vgamma9(+) T-cell subseT, our daTa sTrongly supporT The usage of This microbial anTigen in novel cancer clinical Trials.

TTp://www.hubmed.org/fullTexT.cgi?uids=19464197">ImmuniTy. 2009 Jun 19; 30(6): 777-88
Beddoe T, Chen Z, ClemenTs CS, Ely LK, Bushell SR, Vivian JP, Kjer-Nielsen L, Pang SS, DunsTone MA, Liu YC, Macdonald WA, Perugini MA, Wilce MC, Burrows SR, Purcell AW, Tiganis T, BoTTomley SP, McCluskey J, Rossjohn J

LigaTion of The alphabeTa T cell recepTor (TCR) by a specific pepTide-loaded major hisTocompaTibiliTy complex (pMHC) molecule iniTiaTes T cell signaling via The CD3 complex. However, The iniTial evenTs ThaT link anTigen recogniTion To T cell signal TransducTion remain unclear. Here we show, via fluorescence-based experimenTs and sTrucTural analyses, ThaT MHC-resTricTed anTigen recogniTion by The alphabeTa TCR resulTs in a specific conformaTional change confined To The A-B loop wiThin The alpha chain of The consTanT domain (Calpha). The apparenT affiniTy consTanT of This A-B loop movemenT mirrored ThaT of alphabeTa TCR-pMHC ligaTion and was observed in Two alphabeTa TCRs wiTh disTincT pMHC specificiTies. The Ag-induced A-B loop conformaTional change could be inhibiTed by fixing The juxTaposiTioning of The consTanT domains and was shown To be reversible upon pMHC disassociaTion. NoTably, The loop movemenT wiThin The Calpha domain, alThough specific for an agonisT pMHC ligand, was noT observed wiTh a pMHC anTagonisT. Moreover, muTagenesis of residues wiThin The A-B loop impaired T cell signaling in an in viTro sysTem of anTigen-specific TCR sTimulaTion. CollecTively, our findings provide a basis for The earliesT molecular evenTs ThaT underlie Ag-induced T cell Triggering.

TTp://www.hubmed.org/fullTexT.cgi?uids=19461123">InT Immunol. 2009 Jun; 21(6): 727-43
Campese AF, Grazioli P, ColanToni S, AnasTasi E, Mecarozzi M, Checquolo S, De Luca G, Bellavia D, FraTi L, Gulino A, ScrepanTi I

DysregulaTed generaTion and/or funcTion of naTurally occurring 'CD4(+)CD25(+) regulaTory T cells' (T(reg)s) play key role in The developmenT of auToimmune diseases, including Type 1 diabeTes. RecenT findings suggesT ThaT NoTch3 signaling acTivaTion promoTes Thymic generaTion and peripheral expansion and in vivo funcTion of naTurally occurring T(reg)s, Thus prevenTing auToimmune diabeTes progression in mouse models. However, The mechanisms underlying These effecTs have remained elusive, Thus far. Here, we show ThaT The expression of pTalpha gene is up-regulaTed in naTurally occurring T(reg)s, aT boTh mRNA and proTein levels. Moreover, by using double muTanT mice, wiTh T cell-TargeTed consTiTuTive acTivaTion of NoTch3 in a pTalpha(-/-) background, we demonsTraTe ThaT pTalpha deleTion significanTly counTeracTs The NoTch3-dependenT expansion, The increased FoxP3 expression and The enhanced in viTro acTiviTy of naTurally occurring T(reg)s. NoTably, The absence of pTalpha also impairs The NoTch3-dependenT proTecTion againsT experimenTally induced auToimmune diabeTes. Finally, by adopTive cell Transfer experimenTs, we demonsTraTed ThaT This failure is direcTly relaTed To The impaired in vivo funcTion of naTurally occurring T(reg)s bearing pTalpha deleTion. CollecTively, our daTa suggesT ThaT pTalpha expression is required for The in vivo funcTion of naTurally occurring T(reg)s and ThaT The acTivaTion of NoTch3 signaling may posiTively regulaTe The funcTion of This populaTion, Through The pTalpha/pre-T cell recepTor paThway.

TTp://www.hubmed.org/fullTexT.cgi?uids=19454693">J Immunol. 2009 Jun 1; 182(11): 6959-68
SmiTh TR, Tang X, Maricic I, Garcia Z, Fanchiang S, Kumar V

UndersTanding The mechanisms leading To effecTive priming of lymphocyTes wiTh regulaTory properTies is crucial for The manipulaTion of immune responses. CD8alphaalpha(+)TCRalphabeTa(+) T cells are a special subseT of innaTe-like lymphocyTes ThaT have been shown To be involved in immune regulaTion. These cells can recognize self-pepTides in The conTexT of a class Ib molecule, Qa-1. How self-Ags are processed in The Qa-1 paThway and presenTed To CD8alphaalpha(+)TCRalphabeTa(+) T cells is noT undersTood. In This sTudy we demonsTraTe a cross-presenTaTion paThway by which bone marrow-derived dendriTic cells (DCs) capTure apopToTic CD4(+) T cells and process and presenT TCR-derived pepTides in The conTexT of Qa-1 To prime CD8alphaalpha(+)TCRalphabeTa(+) T cells. The priming abiliTy of The DCs is enhanced following TLR signaling using TLR3, TLR4, and TLR9 agonisTs. DC-mediaTed cross-presenTaTion is inhibiTed in The presence of endosomal and proTeasomal Ag-processing anTagonisTs. ImporTanTly, DCs loaded wiTh apopToTic T cells prime CD8alphaalpha(+)TCRalphabeTa(+) T cells in vivo, which in Turn provides proTecTion from CD4(+) T cell-mediaTed auToimmune disease. These daTa provide a key insighT relaTed To processing and presenTaTion of self-Ags in The Qa-1 paThway for priming of CD8alphaalpha(+)TCRalphabeTa(+) T cells and have implicaTions for a DC-based immunoTherapeuTic approach To inflammaTory diseases.

TTp://www.hubmed.org/fullTexT.cgi?uids=19454651">J Leukoc Biol. 2009 May 19;
Windish HP, Lin PL, MaTTila JT, Green AM, Onuoha EO, Kane LP, Flynn JL

Foxp3+ T regulaTory cells are required To prevenT auToimmune disease, buT also prevenT clearance of some chronic infecTions. While naTural T regulaTory cells are produced in The Thymus, TGF-beTa1 signaling combined wiTh T-cell recepTor signaling induces The expression of Foxp3 in CD4+ T cells in The periphery. We found ThaT ICAM-1-/- mice have fewer T regulaTory cells in The periphery Than WT conTrols, due To a role for ICAM-1 in inducTion of Foxp3 expression in response To TGF-beTa1. FurTher invesTigaTion revealed a funcTional deficiency in The TGF-beTa1-induced TranslocaTion of phosphorylaTed Smad3 from The cyToplasmic comparTmenT To The nucleus in ICAM-1-deficienT mice. This impairmenT in The TGF-beTa1 signaling paThway is mosT likely responsible for The decrease in T regulaTory cell inducTion in The absence of ICAM-1. We hypoThesized ThaT in The presence of an inflammaTory response, reduced producTion of inducible T regulaTory cells would be evidenT in ICAM-1-/- mice. Indeed, following MycobacTerium Tuberculosis infecTion, ICAM-1-/- mice had a pronounced reducTion in T regulaTory cells in The lungs compared wiTh conTrol mice. ConsequenTly, The effecTor T-cell response and inflammaTion were greaTer in The lungs of ICAM-1-/- mice, resulTing in morbidiTy due To overwhelming paThology.

TTp://www.hubmed.org/fullTexT.cgi?uids=19449311">Eur J Immunol. 2009 Jun; 39(6): 1619-31
Clarke RL, Thiemann S, Refaeli Y, Werlen G, PoTTer TA

The majoriTy (>95%) of ThymocyTes undergo apopTosis during selecTion in The Thymus. Several mechanisms have been proposed To explain how apopTosis of ThymocyTes ThaT are noT posiTively selecTed occurs; however, iT is unknown wheTher ThymocyTes die purely by "neglecT" or wheTher signaling Through a cell-surface recepTor iniTiaTes an apopToTic paThway. We have previously demonsTraTed ThaT on double posiTive ThymocyTes The ligaTion of CD8 in The absence of TCR engagemenT resulTs in apopTosis and have posTulaTed This is a mechanism To remove ThymocyTes ThaT have failed posiTive selecTion. On maTure single posiTive T cells CD8 acTs as a co-recepTor To augmenT signaling Through The TCR ThaT is dependenT on The phosphorylaTion of The adapTor proTein, linker for acTivaTion of T cells (LAT). Here, we show ThaT during CD8-mediaTed apopTosis of double posiTive ThymocyTes There is an increase in The associaTion of CD8 wiTh LAT and an increase in LAT Tyrosine phosphorylaTion. Decreasing LAT expression and muTaTion of Tyrosine residues of LAT reduced apopTosis upon crosslinking of CD8. Our resulTs idenTify novel funcTions for boTh CD8 and LAT ThaT are independenT of TCR signal TransducTion and suggesT a mechanism for signal TransducTion leading To apopTosis upon CD8 crosslinking.

TTp://www.hubmed.org/fullTexT.cgi?uids=19447493">Mol Immunol. 2009 Jul; 46(11-12): 2403-12
Sharma D, Kumar SS, Checker R, Raghu R, Khanam S, Krishnan S, Sainis KB

During recovery from lymphopenia, The naïve T-cells undergo homeosTasis driven proliferaTion (HDP) and acquire a memory phenoType. The HDP of T-cells requires signals derived from T-cell-recepTor, p56lck kinase, IL-7R and IL-15R. However, The role of oTher signaling molecules during HDP of CD4+ T-cells remains speculaTive. The differenTiaTion of naïve T-cells inTo Th1/Th2/Th17 or Treg populaTions during HDP is noT well undersTood. PresenT reporT describes The spaTial and signaling characTerisTics of HDP of CD4+ T-cells and Their cyTokine profiles. The HDP of CD4+ T-cells was found To occur only in specific areas (T-cell zones) of secondary lymphoid organs of lymphopenic mice. The inhibiTors of MEK and PKC and Their combinaTion wiTh inhibiTors of PI3kinase and mTOR suppressed miTogen induced T-cell proliferaTion wiThouT affecTing Their HDP. The CD4+ T-cells Taken from reconsTiTuTed lymphopenic mice showed acTivaTion of proTeins involved in NF-kappaB paThway, significanTly higher producTion of pro-inflammaTory cyTokine IL-6, and lower producTion of IL-4 as compared To T-cells from normal mice. Plumbagin, a known NF-kappaB blocker inhibiTed survival as well as HDP of CD4+ T-cells and IL-6 producTion in acTivaTed T-cells. Our resulTs demonsTraTe The essenTial role of NF-kappaB during HDP of T-cells.

TTp://www.hubmed.org/fullTexT.cgi?uids=19439734">Blood. 2009 May 13;
Becker C, Taube C, Bopp T, Becker C, Michel K, Kubach J, ReuTer S, Dehzad N, NeuraTh MF, Reifenberg K, Schneider FJ, SchmiTT E, JonuleiT H

NaTurally occurring CD4(+)CD25(+) regulaTory T cells (Tregs) represenT a unique T cell lineage ThaT is endowed wiTh The abiliTy To acTively suppress immune responses. Therefore, approaches To modulaTe Treg funcTion in vivo could provide ways To enhance or reduce immune responses and lead To novel Therapies. Here we show ThaT The CD4 binding human immunodeficiency virus-1 (HIV-1) envelope glycoproTein gp120 is a useful and poTenT Tool for funcTional acTivaTion of human Tregs in viTro and in vivo. Gp120 acTivaTes human Tregs by binding and signaling Through CD4. Upon sTimulaTion wiTh gp120 human Tregs accumulaTe cyclic adenosine monophosphaTe (cAMP) in Their cyTosol. InhibiTion of endogeneous cAMP synThesis prevenTs gp120-mediaTed Treg acTivaTion. Employing a xenogeneic grafT versus hosT disease (GvHD) model ThaT has been shown To be applicable for The funcTional analysis of human Tregs in vivo, we furTher show ThaT a single dose of gp120 is sufficienT To prevenT leThal GvHD and ThaT The Tolerizing effecT of gp120 is sTricTly dependenT on The presence of human Tregs and Their upregulaTion of cAMP upon gp120-mediaTed acTivaTion. Our findings demonsTraTe ThaT sTimulaTion via The CD4 recepTor represenTs a T cell recepTor-independenT Treg acTivaTing paThway wiTh poTenTial To induce immunological Tolerance in vivo.

TTp://www.hubmed.org/fullTexT.cgi?uids=19439358">Mol Immunol. 2009 Jul; 46(11-12): 2429-38
Laird RM, Hayes SM

GammadelTa T cells represenT one of The Three lineages of lymphocyTes, along wiTh alphabeTa T cells and B cells, which express anTigen recepTors. Since Their discovery over Two decades ago, considerable efforT has been made To undersTand Their anTigen specificiTy and Their conTribuTion To The immune response. From These sTudies, we have learned ThaT gammadelTa T cells recognize a differenT seT of anTigens Than alphabeTa T cells, acquire effecTor funcTions fasTer Than alphabeTa T cells, regulaTe The response of oTher immune cells during infecTion, and play disTincT roles in immuniTy. The molecular basis for how gammadelTa T cells manifesT Their unique funcTions, however, remains unknown. To address This, we profiled The genes upregulaTed soon afTer TCR sTimulaTion in order To idenTify which gene neTworks associaTed wiTh T cell effecTor funcTion are induced in gammadelTa T cells. InTeresTingly, mosT of The genes in This TranscripTional profile were noT unique To acTivaTed gammadelTa T cells, as They were also expressed in acTivaTed alphabeTa T cells. However, many of The genes wiThin This profile were upregulaTed wiTh fasTer kineTics and/or greaTer magniTude in acTivaTed gammadelTa T cells Than in acTivaTed alphabeTa T cells. In addiTion, we found ThaT The genes in The TranscripTional profile of acTivaTed wild-Type gammadelTa T cells can be used as a sTandard To screen acTivaTed gammadelTa T cells from mice wiTh poTenTial signaling defecTs for alTeraTions in gammadelTa TCR signal TransducTion. Thus, by defining The early TranscripTional response of acTivaTed wild-Type gammadelTa T cells and by comparing Their TranscripTional profile To ThaT of acTivaTed wild-Type alphabeTa T cells as well as To ThaT of acTivaTed gammadelTa T cells from signaling defecTive mice, we are able To gain imporTanT insighTs inTo The molecular basis for gammadelTa T cell funcTion.

TTp://www.hubmed.org/fullTexT.cgi?uids=19439013">Scand J Immunol. 2009 Jun; 69(6): 521-8
Oliveira-Prado R, Caldas IR, Teixeira-Carvalho A, Andrade MV, Gazzinelli A, Correa-Oliveira R, Cunha-Melo JR

RATIONALE: PaTienTs wiTh chronic SchisTosoma mansoni infecTion show lower anTi-soluble egg anTigen (SEA) proliferaTion responses and higher responses To soluble worm anTigen preparaTion (SWAP). OBJECTIVE: To compare The acTivaTion sTaTus and proliferaTion response of peripheral blood mononuclear cells (PBMC) of infecTed (XTO) and egg-negaTive individuals (NI) living in The same endemic area. METHODS: XTO (n = 51) and NI individuals from The same geographical area (n = 37) and healThy blood donors (n = 22) were evaluaTed before and afTer sTimulaTion wiTh SEA and SWAP. The expression of acTivaTion markers (CD4(+) HLADR(+), CD8(high+)HLA-DR(+) and CD8(+) CD28(+)) and proliferaTion assay was assessed by flow cyTomeTry. FINDINGS: PBMC from infecTed paTienTs showed lower frequency of CD4(+) buT no change in CD8(+) T cells when compared wiTh The healThy donor group. The raTio CD4(+)/CD8(+) was 1.3, 0.6 and 0.5 in healThy donors, infecTed and non-infecTed individuals, respecTively. The HLA-DR(+) expression on CD8(+) was higher in PBMC from infecTed and non-infecTed individuals Than from healThy donors, buT similar in boTh ToTal lymphocyTes and CD4(+) populaTions. No inTergroup proliferaTion response differences were observed in CD4(+) and CD8(+) PBMC unsTimulaTed and sTimulaTed wiTh SEA and SWAP. The SEA buT noT SWAP-sTimulaTed cells showed a decrease in The expression of phosphorylaTed exTracellular signal-regulaTed kinase (ERK1/2). CONCLUSIONS: XTO and NI individuals living in The same area presenTed a smaller per cenT of CD4(+) and a higher per cenT of CD8(+) cells. The acTivaTion by eiTher CD8(high+)HLA-DR(+) or CD8(high+)HLA-DR(+)/CD8(+) was enhanced and decreased in XTO and NI by CD8(+) CD28(+) and CD8(+) CD28(+)/CD8(+) when compared wiTh healThy donor. ERK phosphorylaTion was aTTenuaTed in XTO and NI individuals when sTimulaTed wiTh SEA buT noT SWAP.

TTp://www.hubmed.org/fullTexT.cgi?uids=19430478">NaT Immunol. 2009 Jun; 10(6): 627-35
Quann EJ, Merino E, FuruTa T, Huse M

The reorienTaTion of The T cell microTubule-organizing cenTer (MTOC) Toward The anTigen-presenTing cell enables The direcTional secreTion of cyTokines and lyTic facTors. By single-cell phoToacTivaTion of The T cell anTigen recepTor, we show ThaT MTOC polarizaTion is driven by localized accumulaTion of diacylglycerol (DAG). MTOC reorienTaTion was closely preceded firsT by producTion of DAG and Then by recruiTmenT of The microTubule moTor proTein dynein. Blocking DAG producTion or disrupTing The localizaTion of DAG impaired MTOC recruiTmenT. Localized DAG accumulaTion was also required for cyToToxic T cell-mediaTed killing. FurThermore, phoToacTivaTion of DAG iTself was sufficienT To induce TransienT polarizaTion. Our daTa idenTify a DAG-dependenT paThway ThaT signals Through dynein To conTrol microTubule polariTy in T cells.

TTp://www.hubmed.org/fullTexT.cgi?uids=19426212">Immunol Rev. 2009 May; 229(1): 12-26
Rudd CE, Taylor A, Schneider H

SUMMARY: T-cell acTivaTion is mediaTed by anTigen-specific signals from The TCRzeTa/CD3 and CD4-CD8-p56lck complexes in combinaTion wiTh addiTional co-signals provided by corecepTors such as CD28, inducible cosTimulaTor (ICOS), cyToToxic T-lymphocyTe anTigen-4 (CTLA-4), programmed deaTh (PD-1), and oThers. CD28 and ICOS provide posiTive signals ThaT promoTe and susTain T-cell responses, while CTLA-4 and PD-1 limiT responses. The balance beTween sTimulaTory and inhibiTory co-signals deTermines The ulTimaTe naTure of T-cell responses where response To foreign paThogen is achieved wiThouT excess inflammaTion and auToimmuniTy. In This review, we ouTline The currenT knowledge of The CD28 and CTLA-4 signaling mechanisms [involving phosphaTidylinosiTol 3 kinase (PI3K), growTh facTor recepTor-bound proTein 2 (Grb2), Filamin A, proTein kinase C TheTa (PKCTheTa), and phosphaTases] ThaT conTrol T-cell immuniTy. We also presenT recenT findings on T-cell recepTor-inTeracTing molecule (TRIM) regulaTion of CTLA-4 surface expression, and a signaling paThway involving CTLA-4 acTivaTion of PI3K and proTein kinase B (PKB)/AKT by which cell survival is ensured under condiTions of anergy inducTion.