Michael Croft

..Here, we examine recent data regarding the potential of these molecules as targets for therapy of autoimmune and inflammatory disease...

..The roles of these molecules in initiating and sustaining the T-cell response and in promoting long-lived immunity are discussed...

..Here, I explore how blocking or inducing the signalling pathways that are triggered by these different interactions can be an effective way to modulate immune responses...

..However, two studies have now provided a new perspective in this already complex area, showing not only a crosstalk between these superfamilies but potentially between co-stimulatory and co-inhibitory receptors...

..This review will focus on recent studies of these molecules and discuss their implications...

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..Collectively, these results indicate manipulation of OX40 may be useful in improving cellular immunotherapy regimes for treatment of persistent virus infections...

..OX40 can positively regulate effector function and late accumulation/survival, whereas 4-1BB can initially operate in a negative manner to limit primary CD8 responses...

..2 is the major ligand for the CD28 receptor on VACV-specific CD8 T cells, that B7.2 can promote efficient CD8 T cell priming without B7.1, and that B7.1 and B7.2 can be differentially utilized during antiviral responses...

..Targeting OX40L then has the potential to improve the efficacy of Ag immunotherapy to promote tolerance...

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..Thus, SLAT is required for thymic DN1 cell expansion, T cell activation, and Th1 and Th2 inflammatory responses...

..These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity...

..Thus, OX40 is one of the costimulatory molecules that can contribute signals to regulate the accumulation of Ag-reactive CD8 cells during immune responses...

..These data suggest that PKCtheta can play roles in aspects of both Th2 and Th1 responses, but lung inflammation induced by Th2 cells is more dependent on this protein kinase than lung inflammation induced by Th1 cells...

..Thus, 4-1BB and 4-1BBL have a previously unknown function in limiting myelopoiesis and the development of dendritic cells...

..Our data provide new insight into the source and nature of molecules required for T(FH) cells to direct GC B cell responses...

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..Therefore, FcepsilonRI-inducible 4-1BB plays a costimulatory function together with FcepsilonRI stimulation...

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..Thus, OX40 signals regulate T cell number and viability through the NF-kappaB1 pathway that controls expression and activity of intracellular targets for proliferation and survival...

..However, binding affinity partially predicted protection efficacy and ultimately epitope immunogenicity and recognition of infected cells offered the best correlation...

..Together, our results highlight an important role for MyD88 in initial antiviral CD8 T cell responses and suggest that targeting this pathway may be useful in promoting and sustaining anti-VACV immunity...

..These results demonstrate that the absence of 4-1BB can make CD4 T cells hyperresponsive to protein Ag in vivo, suggesting a new unappreciated negative regulatory role of 4-1BB when expressed on a T cell...

..This may provide some insight into the uniquely pathogenic aspects of Alternaria-associated asthma...

..OX40 therefore represents an important signal for allowing effective cooperation between CD4 and CD8 cells and for promoting cell interplay and tumor rejection where CD8 activity is limiting...

..These results suggest that TRAF5 can limit the induction of Th2 responses, and that TRAF5 can play a role in modulating responses driven by OX40 costimulation...

..These data provide evidence of a pivotal role for PKCtheta in the generation and effector function of autoimmune Th1 cells...

..Taken together, we concluded that inducible Ag-specific LAP(+) Tregs can suppress asthmatic lung inflammation and constitute a mediator of airway tolerance together with Foxp3(+) Tregs...

..These data suggest that unique costimulatory pathways might control alternate antiviral CD8 responses, demonstrating the plasticity of the immune response in utilizing different mechanisms to achieve similar ultimate goals...

..Thus, sustained Survivin expression from costimulatory signaling maintains T cell division over time and regulates the extent of clonal expansion...

..This review summarizes aspects of these TNF/TNFR interactions that are potentially important to immune responses...

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..These studies demonstrate that 4-1BB, and potentially other costimulatory members of the TNFR family, are targets for therapies aimed at augmenting weak T cell responses in elderly immunocompromised individuals...

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..These studies show that OX40/OX40L interactions form a late checkpoint in diabetes development and suggest that these molecules are realistic targets for therapeutic intervention...

..Thus, sustained and periodic PKB signaling has an integral role in regulating T cell longevity...

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..These data demonstrate that OX40 and Bcl-x(L) can control survival of primed CD8 T cells and provide new insights into both regulation of CD8 immunity and control of tumors...

..Thus, Vav1 is selectively required for IL-4 and c-Maf expression, a requirement reflecting, at least in part, the dependence of c-Maf expression on Ca2+/NFAT signaling...

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..Our results suggest that the virulence of a virus dictates costimulatory receptor usage to determine the level of protective CD8+ T cell immunity...

..Moreover, expression of aurora B restored Cd28-/- T cell proliferation and promoted inflammation in vivo. These data identify aurora B, along with survivin and mTOR, as a regulator of the G1-S checkpoint in T cells...

..Thus, by recruiting TCR-related intracellular molecules into the TRAF2 complex, OX40 provides the T cell with a high level of NF-?B activity needed for longevity...

..Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission...

..Airway tolerance is critical for protecting the lung from inflammatory disease driven by allergens. However, factors that disrupt tolerance processes and then lead to susceptibility to developing allergic asthma remain elusive...

..Evidence is presented for a novel surface FcepsilonRIhi , MHC II +, and c-kit + pure mast cell subset, temporally restricted as antigen-presenting cells in the immune axis of T-cell activation...

..Collectively, our results demonstrate a critical role of HVEM signals in the persistence of large pools of memory CD4 T cells...

..These data suggest that agonists to the OX40 costimulatory receptor represent potential candidates for incorporation into vaccines for respiratory viruses...

..Development of antigen-specific strategies to treat or prevent type 1 diabetes has been slow and difficult because of the lack of experimental tools and defined biomarkers that account for the underlying therapeutic mechanisms...

..These negative regulatory functions of Btk in dendritic cells appear to be mediated mainly through autocrine secretion of IL-10 and subsequent activation of Stat3...

..In this review we discuss these new developments in the context of past research and current models for the generation, persistence, and re-activation of memory T cells...

..These data identify OX40 as a negative regulator of Foxp3 and suggest that OX40 can concomitantly promote effector T cell generation while antagonizing the differentiation of adaptive Foxp3(+) regulatory T cells...

..This study suggests that MEKK1-JNK signaling regulates Itch E3 ligase-mediated tolerogenic process in Th2 cells. These findings have therapeutic implications for allergic diseases...

..This review specifically focuses on recent studies of regulatory T cells, and regulatory or suppressive activity, that are modulated by OX40 or 4-1BB...

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..Altogether, these results chart the way for novel prevention and intervention strategies for viral myocarditis...

..Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity...

..Thus, our data demonstrate that 4-1BB and 4-1BBL do not play a strong or dominant role in driving the generation of high frequencies of VACV-specific CD8 T cells...

..Collectively, the results indicate that preferential replication of VACV in the ovaries may not be dependent on immune suppressive mechanisms in this tissue...

..Thus, OX40-OX40L interactions are pivotal to the efficiency of recall responses regulated by memory Th2 cells...

..In this review, we discuss their control of the generation, persistence, and reactivation of CD8 T cells during virus infection...

..In this review, we will summarize the results of basic research on 4-1BB and 4-1BB immunotherapy of disease and provide some potential mechanistic insights into the many stimulatory and regulatory functions of 4-1BB...

..Therefore, OX40 primarily functions to augment PKB signaling in T cells by enhancing the amount of PI3K and PKB available to the TCR. This highlights a quantitative role of this TNFR family second signal to supplement signal 1...

..Taken together, these results highlight fundamental differences in immunodominance of CD4(+) and CD8(+) T cell responses to a complex pathogen...

..These findings demonstrate that 4-1BB contributes to clonal expansion, survival, and development of Tc1 cells when protein antigen is encountered by primary CD8 T cells in an inflammatory environment in vivo...

..Ultimately, this mechanism may permit regulation of pathogenic Th1 responses by CD8 T regulatory cells...

..Taken together, the data indicate that CD137 and adjuvant combined therapy is an efficacious vaccine strategy for immunization with non-replicating inert antigen...

..Therefore, dual costimulation through CD137 and CD134 drives production and survival of supereffector CD8 T cells through a distinct IL-7-dependent pathway...

..These data demonstrate that CD4( +) T cells can be primed in the absence of functional DC and suggest that relB may gauge the T cell response in vivo...

..Thus, cross-priming of therapeutic CD8(+) T cells by a tumor vaccine transduced with GM-CSF requires TNFR, IL-12, and CD28 signaling...

..Moreover, it will aid in defining how T cell responses can be effectively targeted for vaccination or therapeutic purposes depending on the type of T cell and the stage in the life of the T cell. ..

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..By understanding how OX40 controls the balance of effector/pathogenic T cells and regulatory T cells that suppress immune responses, this will aid in future strategies that might target human disease. ..

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..These studies will show the role of 0X40 in determining peripheral tolerance in both CD4 and CD8 compartments, and whether 0X40 is a viable target for reversing the tolerance process in disease. ..

..Finally, the role of Ox-40/Ox-40L and 4-1BB/4-1BBL interactions in collagen-induced arthritis will be tested. ..

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