The PV-1monoclonal antibody reacts with mouse CD28，a45kDa costimulatory receptor and a member of the Ig superfamily.CD28is expressed by thymocytes，most peripheral T cells，and NK cells.CD28is a receptor forCD80（B7-1）and CD86（B7-2）。Signaling through CD28augments IL-2and IL-2receptor expression as well as cytotoxicity of CD3-activated T cells.The PV-1antibody has been shown to stimulate the proliferation and cytokine production by activated T and NK cells。
Huang，Y.，et al.（2015）。“CRK proteins selectively regulate T cell migration into inflamed tissues”J Clin Invest125（3）：1019-1032。PubMed
Effector T cell migration into inflamed sites greatly exacerbates tissue destruction and disease severity in inflametory diseases，including graft-versus-host disease（GVHD）。T cell migration into such sites depends heavily on regulated adhesion and migration，but the signaling pathways that coordinate these functions downstream of chemokine receptors are largely unknown.Using conditional knockout mice，we found that T cells lacking the adaptor proteins CRK and CRK-like（CRK-like）pendent adhesion，chemotaxis，and diapedesis.Moreover，these two closely related proteins exhibited substantial functional redundancy to，toactivate the integrin regulatory GTPase RAP1.CRK proteins were required for effector T cell trafficking into sites of inflammation，but not for migration to lymphoid organs.In a murine bone marrow transplantation model，the differential migration of CRK/CRKL-deficient T cells resulted in efficient grantation model，the diffiential mins imal GVHD.Together，the results from our studies show that CRK family proteins selectively regulate T cell adhesion and migration at effector sites and suggest that these proteins have potential as therapeutic targets for preventing GVHD。
in vitroT cell stimulation/activation
Klimatcheva，E.，et al.（2015）。“CXCL13antibody for the treatment of autoimmune disorders”BMC Immunol16:6。PubMed
BACKGROUND:Homeostatic B Cell-Attracting chemokine1（BCA-1）otherwise known as CXCL13is constitutively expressed in secondary lymphoid organs by follicular dendritic cells（FDC）and macrophages。It is the only known ligand for the CXCR5 receptor，which is expressed on mature B cells，follicular helper T cells（Tfh），Th17cells and regulatory T（Treg）cells。Aberrant expression of CXCL13within ectopic germinal centers has been linked to the development of autoimmune disorders（e.g.Rheumatoid Arthritis，Multiple Sclerosis，Systemic Lupus Erythematosis）.We，therefore，hypothesized that antibody-mediated disruption of the CXCL13signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression.Thwork describes of inclical-CXCL13antibodyAb5261and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity.RESULTS:We developed a human IgG1monoclonal antibody，MAb5261 that specifically binds to human，rodent and primate CXCL13with an affinity of approximately5nM and capable of CLiviting of from these various speci在，在in vitrofunctional assays.Forin vivostudies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions.Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with4-Hydroxy-3-nitrophenylacetyl hapten conjugated Kenized-KLH）and，in adoptive transfer studies，interfered with the trafficking of B cells to the B cell areas of mouse spleen.Furthermore，this mouse anti-CXCL13antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis（Collagen-Induceed Arthritis（CIA））and Th17-mediated murine model of Multiple Sclerosis（passively-induced Experimental Autommune Encephalomyelitis（EAE））。CONCLUSIONS:We developed anover therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders。
in vitroT cell stimulation/activation
Bertin，S.，et al.（2015）。“Dual-specificity phosphatase6regulates CD4+T-cell functions and restrains spontaneous colitis in IL-10-deficient mice”Mucosal Immunol8（3）：505-515。PubMed
Mitogen-activated protein kinase（MAPK）phosphatases are dual-specificity phosphatases（DUSPs）that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs。DUSP6preferentially dephosphorylates extracellular signal-regulated kinases1and2（ERK1/2）rendering them inactive。Here，we study the role of DUSP6in CD4（+）T-cell function，differentiation，and inflammatory简介in the colon.Upon T-cell receptor（TCR）stimulation，DUSP6knockout（Dusp6（-/-）CD4（+）T cells showed increased ERK1/2 activation，proliferation，Thelper1differentiation，and interferon-gamma production，aswell as a marked decrease in survival，interleukin-17A（IL-17A）secretion，and regulatory T-cell function.To analyze the role of DUSP6in vivo单击功能区上，we employed the Il10（-/-）model of colitis and generated Il10（-/-）/Dusp6（-/-）double-knockout mice。Il10（-/-）/Dusp6（-/-）mice suffered from accelerated and exacerbated spontaneous colitis，which was prevented by ERK1/2 inhibition.ERK1/2 inhibition also augmented regulatory T-cell differentiationin vitroand，andin vivoin both C57Bl/6and Dusp6（-/-）mice。In summary，DUSP6regulates CD4（+）T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2activation。DUSP6might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases，such as inflammatory bowel disease。
in vitroT cell stimulation/activation
Pallandre，J.R.，et al.（2015）。“Novel aminotetrazole derivatives as selective STAT3non-peptide inhibitors”Eur J Med Chem103:163-174。PubMed
The development of inhibitors blocking STAT3transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases.In this context，the selectivity of inhibitors against the STAT1transcription factor is crucial as as STAT3and STAT1play opposite roles in the aptos of itors of intumotucellation ofsponse.A structure-based virtual screening followed by aluciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor.An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established.Optimitation of the timization of the 23 is compound inhibits growth and survival of cells with STAT3signaling pathway while displaying a minimal effect on STAT1signaling.Moreover，it prevents lymphocyte T polarization into Th17and Treg withot affecting their differentation into Th1lymphocyte。
Central nervous system（CNS）autoimmunity is regulated by the balance of pro-inflammatory cytokines and IL-10。Here we identify the transcriptional regulator Blimp1as crucial to induce IL-10in inflammatory Thelper cells.Pre-committed Th17cells respond to IL-27and IL-12by upregulating Blimp1and adopt a Tr-1-like phenotype characterized by IL-10and IFN-gamma productionAcduction.active-coffient，ector T cells fail to produce IL-10，and deficiency in Tr-1cell function leads to uncontrolled Th17cell-driven CNS pathology without the need to stabilize the Th17phenotype with IL-23.IL-23counteracts IL-27and IL-12-mediated effects on Tr-1-development reinforcing the pro-inflammatory phenotype of Thcells.ThIL-12/IL-27signals into CD4（+）effector T cellsdetermines whether tissue inflammation is perpetuated or resolves。
in vitroT cell stimulation/activation
Bertin，S.，et al.（2014）。“The ion channel TRPV1regulates the activation and proinflammatory properties of CD4（+）T cells”Nat Immunol15（11）：1055-1063。PubMed
TRPV1is a Ca（2+）-permeable channel studied mostly as a pain receptor in sensory neurons。However，its role in other cell types is poorly understood.Here we found that TRPV1was functionally expressed in CD4（+）T cells，where it acted as anon-store-operated Ca（2+）channel and contributed to T cell antigen receptor（TCR）-induced Ca（2+）influx，TCR signaling and T cell activation.In models of T cell-mediated colitis，TRPV1promoted colitogenic T cell responses and intestinal inflammation.Furthermore，genetic and pharmacological inhibition of TRPV1in human CD4（+）T cells recapitulated the phenotype of mouse Trpv1（-CD）。Our findings suggest that inhibition of TRPV1could represent anew therapeutic strategy for restraining proinflammatory T cell responses。
in vitroT cell stimulation/activation
Vegran，F.，et al.（2014）。“The transcription factor IRF1dictates the IL-21-dependent anticancer functions of TH9cells”Nat Immunol15（8）：758-766。PubMed
The TH9 subset of helper T cells was initially shown to contribute to the induction of autoimmune and allergic diseases，but subsequent evidence has suggested that these cells also exert antitumor activities.However，the molecular events that account for their effector properties are elusive.HeRF went 1 enhanced the effector function of TH9cells and dictated their anticancer properties.Under TH9-skewing conditions，interleukin1beta（IL-1beta）induced phosphorylation of the transcription factor STAT1and subsequent expression of IRF1，which bound to the promoters of Il9and Il21and enhanced secretion of the cytokines IL-9and IL-21 from TH9cells.Furthermore，IL-1beta-induced TH9cells exerted potent anticancer functions in an IRF1-and IL-21-dependent THmanner.Our findings thus identify IRF1a target for for function of ling。
in vitroT cell stimulation/activation
Chen，E.J.，et al.（2013）。“Ezrin and moesin are required for efficient T cell adhesion and homing to lymphoid organs”PLoS One8（2）：e52368。PubMed
T cell trafficking between the blood and lymphoid organs is a complex，multistep process that requires several high ly dynamic and coordinated changes in cyto-architecture.Members of the ezrin，radixin and moesin（ERM）family of actin-binding proteins have been impled in in in several aspects of this，but studies have yielded conflicting results.Using mice with a conditional deletion of ezrin in CD4+cells and moesin-specific siRNA，we generated T cells lacking ERM proteins，and investigated the effect on specific events requireed forT cell trafficking.ERM-deficient T cells migradermandmunollinin vitroand，andin vivoassays，and could undergo efficient diapedesisin vitro.However，these cells were impaired in their ability to adhere to the beta1integrin ligand fibronectin，and to polarize appropriately in response to fibronectin and VCAM-1binding.This defect was specific for beta1integrins，as adhesion and polarization in response to ICAM-1were normal.In vivo，ERM-decited mins ymphoidorgans.Taken together，these results show that ERM proteins are largely dispensable for T cell chemotaxis，but are important for beta1integrin function and homing to lymphoid organs。
in vitroT cell stimulation/activation
Berger，H.，et al.（2013）。“SOCS3transactivation by PPARgamma prevents IL-17-driven cancer growth”Cancer Res73（12）：3578-3590。PubMed
Activation of the transcription factor PPARgamma by the n-3 fatty acid docosahexaenoic acid（DHA）is implicated in controlling proinflammatory cytokine secretion，but the intracellular signaling pathways engaged by PPARgamma are incompletely characterized.Here，we identify the adapter-encoding gene SOCS3as a critical transcriptional target of PPARgamma.SOCS3promoter binding and gene transactivation by PPARTHgamma was associated with a repression in differentiation of promatory in in formatory hetimatory cells。Accordingly，TH17cells inducedin vitrodisplayed increased SOCS3expression and diminished capacity to produce interleukin（IL）-17following activation of PPARgamma by DHA。Furthermore，naive CD4T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH 17cells.In two different mouse models of cancer，DHA prevented tumoroutgrowth and angiogenesis in an IL-17-dependent manner.Altogether，our results uncover a nothmover nowy mma-induced SOCS3 expression prevents IL-17-mediated cancer growth。
in vitroT cell stimulation/activation
Nowak，E.C.，et al.（2009）。“IL-9as a mediator of Th17-driven inflammatory disease”J Exp Med206（8）：1653-1660。PubMed
TGF beta，Th17cells also produce interleukin（IL）9。Th17cells generatedin vitrowith IL-6and TGF-beta as well as purified ex vivo Th17cells both produced IL-9.To determine if IL-9has functional consequences in Th17-mediated inflammatory disease，we valuated the role of IL-9in the development and progression of experimental autoimneencephomyelitis，mulalitis，multa data show that IL-9 neutralization and IL-9 receptor deficiency attenuates disease，and this correlates with decreases in Th17 cells and IL-6-producing macrophages in the central nervous system，as well as mast cell numbers in the regional lymph nodes.Collectively，these data implicate IL-9 as a Th17-rivematokin to trivat ory disease。
