Several members of the tumor necrosis factor receptor (TNFR) family function after initial T cell activation to sustain T cell responses. This review focuses on CD27, 4-1BB (CD137), OX40 (CD134), HVEM, CD30, and GITR, all of which can have costimulatory effects on T cells. The effects of these costimulatory TNFR family members can often be functionally, temporally, or spatially segregated from those of CD28 and from each other. The sequential and transient regulation of T cell activation/survival signals by different costimulators may function to allow longevity of the response while maintaining tight control of T cell survival. Depending on the disease condition, stimulation via costimulatory TNF family members can exacerbate or ameliorate disease. Despite these complexities, stimulation or blockade of TNFR family costimulators shows promise for several therapeutic applications, including cancer, infectious disease, transplantation, and autoimmunity.

Tnf/tnfr family members in costimulation of t cell responses

Eph-ephrin bidirectional signaling in physiology and disease.

We recently showed that dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) prime naive CD4 + T cells to differentiate into T helper type 2 (Th2) cells that produced high amounts of tumor necrosis factor- α (TNF- α ), but no interleukin (IL)-10 Here we report that TSLP induced human DCs to express OX40 ligand (OX40L) but not IL-12 TSLP-induced OX40L on DCs was required for triggering naive CD4 + T cells to produce IL-4, -5, and -13 We further revealed the following three novel functional properties of OX40L: (a) OX40L selectively promoted TNF- α , but inhibited IL-10 production in developing Th2 cells; (b) OX40L lost the ability to polarize Th2 cells in the presence of IL-12; and (c) OX40L exacerbated IL-12–induced Th1 cell inflammation by promoting TNF- α , while inhibiting IL-10 We conclude that OX40L on TSLP-activated DCs triggers Th2 cell polarization in the absence of IL-12, and propose that OX40L can switch IL-10–producing regulatory Th cell responses into TNF- α –producing inflammatory Th cell responses

/pdf/tslp-activated-dendritic-cells-induce-an-inflammatory-t-1lf5vnz4x7.pdf

TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand

Interactions between co-stimulatory ligands and their receptors are crucial for the activation of T cells, the prevention of tolerance and the development of T-cell immunity. It is now evident that members of the immunoglobulin-like CD28–B7 co-stimulatory family cannot fully account for an effective long-lasting T-cell response or the generation of memory T cells. Several members of the tumour-necrosis factor receptor (TNFR) superfamily — OX40, 4-1BB, CD27, CD30 and HVEM (herpes-virus entry mediator) — are poised to deliver co-stimulatory signals both early and late after encounter with antigen. The roles of these molecules in initiating and sustaining the T-cell response and in promoting long-lived immunity are discussed.

Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?

The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunbiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2567.2005.02143.x

The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games

The interaction between OX40 and OX40 ligand (OX40L) is suggested to provide T cells with an effective costimulatory signals during T cell-APC interaction. To examine the in vivo effect of constitutive OX40/OX40L interaction during immune regulation, we report the establishment of OX40L-transgenic (OX40L-Tg) mice that constitutively express OX40L on T cells. Markedly elevated numbers of effector memory CD4 + T cells, but not CD8 + T cells, were observed in the secondary lymphoid organs of OX40L-Tg mice. Upon immunization with keyhole limpet hemocyanin in the absence of adjuvant, profound T cell proliferative responses and cytokine productions were seen in the OX40L-Tg mice as compared with wild-type mice. Furthermore, in OX40L-Tg mice administrated with superantigen, this constitutive OX40/OX40L interaction on CD4 + T cells completely prevented normal in vivo clonal T cell deletion. Interestingly, OX40L-Tg mice on the C57BL/6 background spontaneously developed interstitial pneumonia and inflammatory bowel disease that was accompanied with a significant production of anti-DNA Ab in the sera. Surprisingly, these diseases were not evident on the OX40L-Tg mice on the BALB/c strain. However, such inflammatory diseases were successfully reproducible in recombination-activating gene (RAG)2-deficient mice upon transfer of OX40L-Tg CD4 + T cells. Blockade of OX40/OX40L interaction in the recipient RAG2-deficient mice completely prevented disease development. The present results orchestrated in this study indicate that OX40/OX40L interaction may be a vital link in our understanding of T cell-mediated organ-specific autoimmunity.

Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases

OX40 ligand (OX40L) expressed on APCs, and its receptor, OX40 present on activated T cells, are members of the TNF/TNFR family, respectively, and have been located at the sites of inflammatory conditions. We have observed in OX40L-deficient mice (OX40L−/−) an impaired APC capacity and in our recently constructed transgenic mice expressing OX40L (OX40L-Tg), a markedly enhanced T cell response to protein Ags. Using these mice, we demonstrate here the critical involvement of the OX40L-OX40 interaction during the T cell priming events in the occurrence of experimental autoimmune encephalomyelitis (EAE). In OX40L−/− mice, abortive T cell priming greatly reduced the clinical manifestations of actively induced EAE, coupled with a reduction in IFN-γ, IL-2, and IL-6 production in vitro. Adoptive transfer experiments however revealed an efficient transfer of disease to OX40L−/− mice using wild-type donor T cells, indicating an intact capacity of OX40L−/− mice to initiate effector responses. On the other hand, OX40L−/− donor T cells failed to transfer disease to wild-type recipient mice. Furthermore, OX40L-Tg mice developed a greater severity of EAE despite a delayed onset, while both OX40L-Tg/CD28−/− and OX40L-Tg/CD40−/− mice failed to develop EAE demonstrating a requisite for these molecules. These findings indicate a pivotal role played by OX40L in the pathogenesis of EAE.

/pdf/critical-involvement-of-ox40-ligand-signals-in-the-t-cell-1elscpiow6.pdf

Critical involvement of OX40 ligand signals in the T cell priming events during experimental autoimmune encephalomyelitis.

Convergent extension (CE) movement of cells is one of the fundamental processes that control the organized morphogenesis of tissues and organs. The molecular events connecting the noncanonical Wnt pathway and CE movement, however, are not well understood. We show that subcellular localization of Daam1, an essential component of noncanonical Wnt signaling, changes dynamically during notochord formation. In the early phases, Daam1 complexes with EphB receptors and Disheveled 2. This complex is incorporated into endocytic vesicles in a dynamin-dependent manner, thereby resulting in the removal of EphB from the cell surface with subsequent switching of cell adhesiveness. In the next step, Daam1 colocalizes with the actin cytoskeleton to induce morphological extension of cells. We elucidate the molecular mechanism underlying the CE movement of notochord cells with Daam1 as a dynamic coordinator of endocytosis and cytoskeletal remodeling.

https://www.pnas.org/content/pnas/104/16/6708.full.pdf

Daam1 regulates the endocytosis of EphB during the convergent extension of the zebrafish notochord.

The role of OX40-OX40 ligand (OX40L) interaction in Th cell differentiation remains contentious. In vitro studies have revealed a Th2-biased effect by OX40 signals in T cells. However, in vivo studies demonstrated that OX40-OX40L interaction is involved in responses either Th1 or Th2, or both, which appears to be dependent on the experimental conditions used. We document in our report Th cell differentiation in OX40L-deficient and OX40L-transgenic (Tg) mice in response to protein antigens (Ag) and to Leishmania major (L. major) infection. Upon immunization with protein Ag, we demonstrate the adjuvant effect of OX40 signals during in vivo Th2 responses. However, adjuvant treatment to mice ameliorates the Th2-specific effect of OX40-OX40L interaction and rather induces concurrent promotion of both Th1 and Th2 responses via OX40 signals. Thus, previous reports showing promotion of Th1 response by OX40-OX40L interaction may in actual fact be affected by the adjuvant effects mediated by the various experimental conditions. Indeed, constitutive OX40–OX40L interactions in OX40L-Tg mice converted the normally resistant C57BL/6 strain, into a susceptible status following L. major infection due to an extraordinary elevated Th2 response. These results provide convincing evidence demonstrating that the OX40-OX40L interaction is paramount in the development of Th2 responses in vivo.

Takayuki Sato

Papers

Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases

Critical involvement of OX40 ligand signals in the T cell priming events during experimental autoimmune encephalomyelitis.

Daam1 regulates the endocytosis of EphB during the convergent extension of the zebrafish notochord.

OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses.

An ATEM study of oxidation behavior of SCC crack tips in 304L stainless steel in high temperature oxygenated water