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OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed on the surface of activated T cells. Upon interaction with its cognate ligand, OX40L, OX40 transmits costimulatory signals to antigen-primed T cells, promoting their activation, differentiation, and survival — processes essential for the establishment of adaptive immunity. Although the OX40-OX40L interaction has been extensively studied in the context of disease treatment, developing a substitute for the naturally expressed membrane-bound OX40L, particularly a multimerized OX40L trimers, that effectively regulates OX40-driven T cell responses remains a significant challenge. In this study, we successfully engineered soluble OX40L-fusion proteins capable of robustly activating OX40 on T cells. This was achieved by incorporating functional multimerization domains into the TNF homology domain of OX40L. These OX40L proteins bound to OX40, subsequently activated NF-κB signaling, and induced cytokine production by T cells in vitro . In vivo , mice treated with one of the OX40L-fusion proteins — comprising a single-chain OX40L trimer linked to the C-terminus of the human IgG1 Fc domain, forming a dimer of trimers — exhibited significantly enhanced clonal expansion of antigen-specific CD4 + T cells during the primary phase of the immune response. A comparable antibody-fusion single-chain TNF protein incorporating 4-1BBL, CD70 (CD27L), or GITRL in place of OX40L elicited similar in vivo T cell responses. Thus, we propose that optimizing the multimerization of OX40L proteins through innovative design strategies may facilitate the development of more effective agonists for targeted immunotherapies.

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc−scOX40L, Fc−sc4-1BBL, Fc−scCD27L (CD70) and Fc−scGITRL. Without intentional cross-linking, these soluble Fc−scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc−scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc−scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins.

TNF receptor-associated factors (TRAFs) function as intracellular adaptor proteins utilized by members of the TNF receptor superfamily, such as CD40. Among the TRAF family proteins, TRAF5 has been identified as a potential regulator of CD40. However, it remains unclear whether TRAF5 regulates the generation of germinal center (GC) B cells and antigen-specific antibody production in the T-dependent (TD) immune response. TRAF5-deficient (Traf5−/−) and TRAF5-sufficient (Traf5+/+) mice were immunized in the footpad with 2,4,6-trinitrophenol-conjugated keyhole limpet hemocyanin (TNP-KLH) and complete Freund’s adjuvant (CFA). We found that GC B cell generation and antigen-specific IgM and IgG1 production were significantly impaired in Traf5−/− mice compared to Traf5+/+ mice. The expression levels of CD40-target genes Fas and Lta, which are involved in GC formation, were significantly decreased in B220+ cells isolated from immunized Traf5−/− mice. Traf5−/− B cells showed decreased antibody production, proliferation, and induction of CD40-target genes Tnfaip3, Tnfsf4, and Cd80 in response to agonistic Fc-CD40L protein in vitro. Furthermore, administration of TNP-KLH and Fc-CD40L to Traf5−/− mice resulted in a severe loss of GC B cell development. These results highlight the crucial role of TRAF5 in driving CD40-mediated TD immune response in vivo.

Then as now for El Niño Coarse resolution palaeoclimate proxy evidence has suggested that the Pliocene warm period (PWP) between 3 million and 5 million years ago was characterized by permanent El Niño conditions in which the equatorial Pacific was uniformly warm, instead of having the modern-day 'cold tongue' extending westward from South America. New high-resolution climate proxy data from fossil corals raise doubts over this assertion. Well-preserved PWP-era fossil corals with clear skeletal annual bands, discovered in the Philippines, show that ocean conditions in the western Pacific during the PWP were characterized by El Niño variations that are similar to those we see today. Coarse-resolution palaeoclimate proxy evidence has suggested that the Pliocene warm period (∼3–5 million years ago) was characterized by permanent El Niño conditions in which the equatorial Pacific was uniformly warm, instead of having the modern-day 'cold tongue' extending westward from South America. This study uses high-resolution climate proxy information from fossil corals to challenge this assertion and shows that ocean conditions in the western Pacific during the Pliocene warm period were characterized by El Niño variations similar to modern-day variations. The El Niño/Southern Oscillation (ENSO) system during the Pliocene warm period (PWP; 3–5 million years ago) may have existed in a permanent El Niño state with a sharply reduced zonal sea surface temperature (SST) gradient in the equatorial Pacific Ocean 1 . This suggests that during the PWP, when global mean temperatures and atmospheric carbon dioxide concentrations were similar to those projected for near-term climate change 2 , ENSO variability—and related global climate teleconnections—could have been radically different from that today. Yet, owing to a lack of observational evidence on seasonal and interannual SST variability from crucial low-latitude sites, this fundamental climate characteristic of the PWP remains controversial 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . Here we show that permanent El Niño conditions did not exist during the PWP. Our spectral analysis of the δ 18 O SST and salinity proxy, extracted from two 35-year, monthly resolved PWP Porites corals in the Philippines, reveals variability that is similar to present ENSO variation. Although our fossil corals cannot be directly compared with modern ENSO records, two lines of evidence suggest that Philippine corals are appropriate ENSO proxies. First, δ 18 O anomalies from a nearby live Porites coral are correlated with modern records of ENSO variability. Second, negative-δ 18 O events in the fossil corals closely resemble the decreases in δ 18 O seen in the live coral during El Niño events. Prior research advocating a permanent El Niño state may have been limited by the coarse resolution of many SST proxies, whereas our coral-based analysis identifies climate variability at the temporal scale required to resolve ENSO structure firmly.