Kegg Pathway: T cell receptor signaling pathway

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).

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 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.

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=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=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=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.

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.

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.

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.

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.

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.

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.

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.