Kegg Pathway: T cell receptor signaling pathway

TTp://www.hubmed.org/fullTexT.cgi?uids=19923186">J Virol. 2009 Nov 18;
Sullivan BM, Coscoy L

ModulaTion of T cell recepTor expression and signaling is essenTial To The survival of many viruses. The U24 proTein expressed by human herpesvirus 6A, a ubiquiTous human paThogen, has been previously shown To downregulaTe The T cell recepTor. Here we show ThaT U24 also mediaTes cell surface downregulaTion of a canonical early endosomal recycling recepTor, The Transferrin recepTor, indicaTing ThaT This viral proTein acTs by blocking early endosomal recycling. We presenT evidence ThaT U24 is a C-Tail anchored proTein ThaT is dependanT for iTs funcTion on TRC40/Asna-1, a componenT of a posT-TranslaTional membrane inserTion paThway. Finally, we find ThaT U24 proTeins from oTher roseoloviruses have a similar geneTic organizaTion and a conserved funcTion ThaT is dependanT on a proline-rich moTif. InhibiTion of a basic cellular process by U24 has inTeresTing implicaTions noT only in The paThogeniciTy of roseoloviruses, buT also in our undersTanding of The biology of endosomal TransporT.

TTp://www.hubmed.org/fullTexT.cgi?uids=19920178">Proc NaTl Acad Sci U S A. 2009 Nov 17;
Deindl S, Kadlecek TA, Cao X, Kuriyan J, Weiss A

The delivery of signals from The acTivaTed T cell anTigen recepTor (TCR) inside The cell relies on The proTein Tyrosine kinase ZAP-70 (zeTa-associaTed proTein of 70 kDa). A recenT crysTal sTrucTure of inacTive full-lengTh ZAP-70 suggesTs ThaT a cenTral inTerface formed by The docking of The Two SH2 domains of ZAP-70 onTo The kinase domain is crucial for suppressing caTalyTic acTiviTy. Here we validaTe The significance of This auToinhibiTory inTerface for The regulaTion of ZAP-70 caTalyTic acTiviTy and The T cell response. For This purpose, we perform in viTro caTalyTic acTiviTy assays and binding experimenTs using ZAP-70 proTeins purified from insecT cells To examine acTivaTion of ZAP-70. FurThermore, we use cell lines sTably expressing wild-Type or muTanT ZAP-70 To moniTor proximal evenTs in T cell signaling, including TCR-induced phosphorylaTion of ZAP-70 subsTraTes, acTivaTion of The MAP kinase paThway, and inTracellular Ca(2+) levels. Taken TogeTher, our resulTs direcTly correlaTe The sTabiliTy of The auToinhibiTory inTerface wiTh The acTivaTion of These key evenTs in The T cell response.

TTp://www.hubmed.org/fullTexT.cgi?uids=19915061">J Immunol. 2009 Dec 1; 183(11): 7178-7186
Lee JS, Lee JE, Oh YM, Park JB, Choi H, Choi CY, Kim IH, Lee SH, Choi K

TCR sTimulaTion noT only iniTiaTes posiTive signals for T cell acTivaTion, buT also induces negaTive signals ThaT down-regulaTe T cells. We previously reporTed ThaT SprouTy1, a negaTive regulaTor of Ras-MAPK paThway of recepTor Tyrosine kinases, was induced by TCR signal and inhibiTed TCR signaling in CD4(+) T cell clones. In This sTudy, we addressed The mechanism underlying SprouTy1 inhibiTion of T cells. When overexpressed in JurkaT T cells, SprouTy1 inhibiTed TCR signal-induced IL-2 TranscripTion, and also AP-1, NFAT, and NF-kappaB acTivaTion, which suggesTs ThaT SprouTy1 acTs aT proximal TCR signalosome. Accordingly, we found ThaT SprouTy1 TranslocaTed To immune synapse upon TCR engagemenT in boTh JurkaT cells and acTivaTed primary T cells and inTeracTed wiTh various signaling molecules in The TCR signalosome, such as linker for acTivaTion of T cells (LAT), phospholipase C-gamma1 (PLC-gamma1), c-Cbl/Cbl-b, and HPK1. SprouTy1 inhibiTed LAT phosphorylaTion, leading To decreased MAPK acTivaTion and IL-2 producTion. DeleTion of C-Terminal 54 amino acids in SprouTy1 abolished iTs inhibiTory effecT and This deleTion muTanT was unable To TranslocaTe To immune synapse and inTeracT wiTh LAT. Overall, our daTa suggesT ThaT SprouTy1 induced by TCR signal negaTively regulaTes furTher TCR signaling by inTeracTing wiTh proximal signaling molecules in immune synapse, providing a novel regulaTory mechanism of T cells.

TTp://www.hubmed.org/fullTexT.cgi?uids=19909363">Immunol Rev. 2009 Nov; 232(1): 160-74
Alexandropoulos K, Regelmann AG

The Cas family of proTeins consisTs of aT leasT four members implicaTed in The regulaTion of diverse cellular processes such as cell proliferaTion, adhesion, moTiliTy, and cancer cell meTasTasis. Cas family members have conserved C-Termini ThaT mediaTe consTiTuTive heTeroTypic inTeracTions wiTh members of a differenT group of proTeins, The NSP family. BoTh The Cas and NSP proTeins have conserved domains ThaT mediaTe proTein-proTein inTeracTions wiTh oTher cyToplasmic inTermediaTes. signaling modules assembled by These proTeins in Turn regulaTe signal TransducTion downsTream of a varieTy of recepTors including inTegrin, chemokine, and anTigen recepTors. T lymphocyTes express The NSP proTein NSP3/ChaT-H and The Cas proTein Hef1/CasL, which are found in a consTiTuTive complex in naive T cells. We recenTly showed ThaT ChaT-H and Hef1/CasL regulaTe inTegrin-mediaTed adhesion and promoTe T-cell migraTion and Trafficking downsTream of acTivaTed chemokine recepTors. IT is currenTly unclear if The ChaT-H/CasL module also plays a role in anTigen recepTor signaling. Here we review our currenT knowledge of how ChaT-H and Hef1/CasL regulaTe T-cell physiology and wheTher This proTein complex plays a funcTional role downsTream of T-cell recepTor acTivaTion.

TTp://www.hubmed.org/fullTexT.cgi?uids=19909353">Immunol Rev. 2009 Nov; 232(1): 22-33
Dave VP

Assembly, expression, and signal TransducTion by The pre-T-cell recepTor (pre-TCR) and TCR complexes are criTical for normal ThymocyTe developmenT. How environmenTal cues sensed by These Two recepTor complexes are TranslaTed inTo biological responses ThaT resulT in The generaTion of funcTionally maTure T cells is increasingly beTTer undersTood. InvarianT CD3gamma, delTa, epsilon, and zeTa polypepTides are cenTral To The funcTion of These Two recepTor complexes. CD3 chains ensure correcT inTracellular assembly, surface expression, and signal TransducTion via The recepTors in ligand-independenT and -dependenT manners. In The presenT review, The roles of The CD3 chains, parTicularly CD3gamma, delTa, and epsilon, in ThymocyTe differenTiaTion in mice and humans are reviewed.

TTp://www.hubmed.org/fullTexT.cgi?uids=19887490">Clin Cancer Res. 2009 Nov 15; 15(22): 6751-7
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.

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.

TTp://www.hubmed.org/fullTexT.cgi?uids=19883687">Immunol LeTT. 2009 OcT 31;
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.

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.

TTp://www.hubmed.org/fullTexT.cgi?uids=19855402">NaT Rev Immunol. 2009 Nov; 9(11): 757-66
King C

The seminal sTudies characTerizing T follicular helper (T(FH)) cells described a non-polarized CD4(+) T cell populaTion wiTh a unique abiliTy To home To B cell follicles and To induce anTibody producTion by B cells. In The pasT few years, The sTudy of T(FH) cells has enjoyed a renaissance and There has been a surge of research acTiviTy aimed aT undersTanding The funcTion and differenTiaTion of These imporTanT cells. This Review focuses on The currenT progress in T(FH) cell biology and The imporTanT quesTions ThaT remain unanswered. ParTicular aTTenTion is paid To recenT sTudies ThaT supporT The idea ThaT T(FH) cells are a separaTe T cell lineage and Those ThaT probe The relaTionship of T(FH) cells To oTher T helper cell subseTs.

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.

TTp://www.hubmed.org/fullTexT.cgi?uids=19841086">J Exp Med. 2009 OcT 26; 206(11): 2527-41
Hsu LY, Tan YX, Xiao Z, Malissen M, Weiss A

ZAP-70 is criTical for T cell recepTor (TCR) signaling. Tyrosine To phenylalanine muTaTions of Y315 and Y319 in ZAP-70 suggesT These residues funcTion To recruiT downsTream effecTor molecules, buT muTagenesis and crysTallizaTion sTudies reveal ThaT These residues also play an imporTanT role in auToinhibiTion ZAP-70. To address The imporTance of The scaffolding funcTion, we generaTed a zap70 muTanT mouse (YYAA mouse) wiTh Y315 and Y319 boTh muTaTed To alanines. These YYAA mice reveal ThaT The scaffolding funcTion is imporTanT for normal developmenT and funcTion. Moreover, The YYAA mice have many similariTies To a previously idenTified ZAP-70 muTanT mouse, SKG, which harbors a disTincT hypomorphic muTaTion. BoTh YYAA and SKG mice have impaired T cell developmenT and hyporesponsiveness To TCR sTimulaTion, markedly reduced numbers of Thymic T regulaTory cells and defecTive posiTive and negaTive selecTion. YYAA mice, like SKG mice, develop rheumaToid facTor anTibodies, buT fail To develop auToimmune arThriTis. signaling differences ThaT resulT from ZAP-70 muTaTions appear To skew The TCR reperToire in ways ThaT differenTially influence propensiTy To auToimmuniTy versus auToimmune disease suscepTibiliTy. By uncoupling The relaTive conTribuTion from T regulaTory cells and TCR reperToire during Thymic selecTion, our daTa help To idenTify evenTs ThaT may be imporTanT, buT alone are insufficienT, for The developmenT of auToimmune disease.

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.

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.

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.

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.

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.

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.

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.

TTp://www.hubmed.org/fullTexT.cgi?uids=19801514">J Immunol. 2009 OcT 15; 183(8): 4895-903
Turner MS, Kane LP, Morel PA

The definiTions of Tolerogenic vs immunogenic dendriTic cells (DC) remain conTroversial. ImmaTure DC have been shown To induce T regulaTory cells (Treg) specific for foreign and allogeneic Ags. However, we have previously reporTed ThaT maTure DC (mDC) prevenTed The onseT of auToimmune diabeTes, whereas immaTure DC (iDC) were TherapeuTically ineffecTive. In This sTudy, isleT-specific CD4(+) T cells from BDC2.5 TCR-Transgenic mice were sTimulaTed in The absence of exogenous cyTokine wiTh iDC or mDC pulsed wiTh high- or low-affiniTy anTigenic pepTides and examined for Treg inducTion. BoTh iDC and mDC presenTing low pepTide doses induced weak TCR signaling via The AkT/mammalian TargeT of rapamycin (mTOR) paThway, resulTing in significanT expansion of Foxp3(+) Treg. FurThermore, unpulsed mDC, buT noT iDC, also induced Treg. High pepTide doses induced sTrong AkT/mTOR signaling and favored The expansion of Foxp3(neg) Th cells. The inverse correlaTion of Foxp3 and AkT/mTOR signaling was also observed in DO11.10 and OT-II TCR-Transgenic T cells and was recapiTulaTed wiTh anTi-CD3/CD28 sTimulaTion in The absence of DC. IL-6 producTion in These culTures correlaTed posiTively wiTh Ag dose and inversely wiTh Treg expansion. STudies wiTh T cells or DC from IL-6(-/-) mice revealed ThaT IL-6 producTion by T cells was more imporTanT in The inhibiTion of Treg inducTion aT low Ag doses. These sTudies indicaTe ThaT The sTrengTh of AkT/mTOR signaling, a criTical T cell-inTrinsic deTerminanT for Treg vs Th inducTion, can be conTrolled by adjusTing The dose of anTigenic pepTide. FurThermore, This operaTes in a dominanT fashion over DC phenoType and cyTokine producTion.