The adaptor TRAF5 limits the differentiation of inflammatory CD4(+) T cells by antagonizing signaling via the receptor for IL-6.

The physiological functions of members of the tumor-necrosis factor (TNF) receptor (TNFR)-associated factor (TRAF) family in T cell immunity are not well understood. We found that in the presence of interleukin 6 (IL-6), naive TRAF5-deficient CD4(+) T cells showed an enhanced ability to differentiate into the TH17 subset of helper T cells. Accordingly, TH17 cell-associated experimental autoimmune encephalomyelitis (EAE) was greatly exaggerated in Traf5(-/-) mice. Although it is normally linked with TNFR signaling pathways, TRAF5 constitutively associated with a cytoplasmic region in the signal-transducing receptor gp130 that overlaps with the binding site for the transcription activator STAT3 and suppressed the recruitment and activation of STAT3 in response to IL-6. Our results identify TRAF5 as a negative regulator of the IL-6 receptor signaling pathway that limits the induction of proinflammatory CD4(+) T cells that require IL-6 for their development.

Transmembrane helix 6 of ABCD4 is indispensable for cobalamin transport.

ABCD4, which belongs to the ABC protein subfamily D, plays a role in the transport of cobalamin from lysosomes to the cytosol by cooperating with ATP-binding and ATP-hydrolysis. Pathogenic variants in the ABCD4 gene lead to an inherited metabolic disorder characterized by cobalamin deficiency. However, the structural requirements for cobalamin transport in ABCD4 remain unclear. In this study, six proteoliposomes were prepared, each containing a different chimeric ABCD4 protein, wherein each of the six transmembrane (TM) helices was replaced with the corresponding ABCD1. We analyzed the cobalamin transport activities of the ABCD mutants. In the proteoliposome with chimeric ABCD4 replacing TM helix 6, the cobalamin transport activity disappeared without a reduction in ATPase activity, indicating that TM helix 6 contributes to substrate recognition. Furthermore, the substitution of aspartic acid at position 329 or threonine at position 332 in TM helix 6 with the basic amino acid lysine led to a decrease in cobalamin-transport activity without causing a reduction in ATPase activity. The amino acids in TM helix 6 may be critically involved in substrate recognition; the charged state in the C-terminal half of TM helix 6 of ABCD4 is responsible for cobalamin transport activity.

Increased neurotoxicity of high-density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very-long-chain fatty acid transporter Abcd1.

X-linked adrenoleukodystrophy (X-ALD) is a genetic neurodegenerative disorder caused by pathogenic variants in ABCD1, resulting in the accumulation of very-long-chain fatty acids (VLCFAs) in tissues. The etiology of X-ALD is unclear. Activated astrocytes play a pathological role in X-ALD. Recently, reactive astrocytes have been shown to induce neuronal cell death via saturated lipids in high-density lipoprotein (HDL), although how HDL from reactive astrocytes exhibits neurotoxic effects has yet to be determined. In this study, we obtained astrocytes from wild-type and Abcd1-deficient mice. HDL was purified from the culture supernatant of astrocytes, and the effect of HDL on neurons was evaluated in vitro. To our knowledge, this study shows for the first time that HDL obtained from Abcd1-deficient reactive astrocytes induces a significantly higher level of lactate dehydrogenase (LDH) release, a marker of cell damage, from mouse primary cortical neurons as compared to HDL from wild-type reactive astrocytes. Notably, HDL from Abcd1-deficient astrocytes contained significantly high amounts of VLCFA-containing phosphatidylcholine (PC) and LysoPC. Activation of Abcd1-deficient astrocytes led to the production of HDL containing decreased amounts of PC with arachidonic acid in sn-2 acyl moieties and increased amounts of LysoPC, presumably through cytosolic phospholipase A2 α upregulation. These results suggest that compositional changes in PC and LysoPC in HDL, due to Abcd1 deficiency and astrocyte activation, may contribute to neuronal damage. Our findings provide novel insights into central nervous system pathology in X-ALD.

TNF Receptor-Associated Factor 5 Limits IL-27 Receptor Signaling in CD4+ T Lymphocytes.

TNF receptor-associated factor 5 (TRAF5) restrains early signaling activity of the IL-6 receptor in naive CD4+ T cells by interacting with the shared gp130 chain, although TRAF5 was initially discovered as a cytoplasmic adaptor protein to activate signaling mediated by TNF receptor family molecules. This leads to the question of whether TRAF5 limits signaling via the receptor for IL-27, which is composed of gp130 and WSX-1. The aim of this study is to clarify the role of TRAF5 in IL-27 receptor signaling and to understand the differential role of TRAF5 on cytokine receptor signaling. We found that Traf5 -/- CD4+ T cells displayed significantly higher levels of phosphorylated STAT1 and STAT-regulated genes Socs3 and Tbx21, as early as 1 h after IL-27 exposure when compared with Traf5 +/+ CD4+ T cells. Upon IL-27 and TCR signals, the Traf5 deficiency significantly increased the induction of IL-10 and promoted the proliferation of CD4+ T cells. Traf5 -/- mice injected with IL-27 displayed significantly enhanced delayed-type hypersensitivity responses, demonstrating that TRAF5 works as a negative regulator for IL-27 receptor signaling. In contrast, IL-2 and proliferation mediated by glucocorticoid-induced TNF receptor-related protein (GITR) and TCR signals were significantly decreased in Traf5 -/- CD4+ T cells, confirming that TRAF5 works as a positive regulator for cosignaling via GITR. Collectively, our results demonstrate that TRAF5 reciprocally controls signals mediated by the IL-27 receptor and GITR in CD4+ T cells and suggest that the regulatory activity of TRAF5 in gp130 is distinct from that in TNF receptor family molecules in a T cell.

The immunological significance of tumor necrosis factor receptor-associated factors (TRAFs).

The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of molecules are intracellular signaling adaptors and control diverse signaling pathways mediated not only by the TNFR superfamily and the Toll-like receptor/IL-1 receptor superfamily but also by unconventional cytokine receptors such as IL-6 and IL-17 receptors. There are seven family members, TRAF1 to TRAF7, in mammals. Exaggerated immune responses induced through TRAF signaling downstream of these receptors often lead to inflammatory and autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoinflammatory syndromes, and thus those signals are major targets for therapeutic intervention. For this reason, it has been very important to understand signaling mechanisms regulated by TRAFs that greatly impact on life/death decisions and the activation, differentiation and survival of cells of the innate and adaptive immune systems. Accumulating evidence suggests that dysregulated cellular expression and/or signaling of TRAFs causes overproduction of pro-inflammatory cytokines, which facilitates aberrant activation of immune cells. In this review, I will explain the structural and functional aspects that are responsible for the cellular activity and disease outcomes of TRAFs, and summarize the findings of recent studies on TRAFs in terms of how individual TRAF family molecules regulate biological and disease processes in the body in both positive and negative ways. This review also discusses how TRAF mutations contribute to human disease.

The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro.

Vitamin B12 (cobalamin) is an essential micronutrient for human health, and mutation and dysregulation of cobalamin metabolism are associated with serious diseases, such as methylmalonic aciduria and homocystinuria. Mutations in ABCD4 or LMBRD1, which encode the ABC transporter ABCD4 and lysosomal membrane protein LMBD1, respectively, lead to errors in cobalamin metabolism, with the phenotype of a failure to release cobalamin from lysosomes. However, the mechanism of transport of cobalamin across the lysosomal membrane remains unknown. We previously demonstrated that LMBD1 is required for the translocation of ABCD4 from the endoplasmic reticulum to lysosomes. This suggests that ABCD4 performs an important function in lysosomal membrane cobalamin transport. In this study, we expressed human ABCD4 and LMBD1 in methylotrophic yeast and purified them. We prepared ABCD4 and/or LMBD1 containing liposomes loaded with cobalamin and then quantified the release of cobalamin from the liposomes by reverse-phase HPLC. We observed that ABCD4 was able to transport cobalamin from the inside to the outside of liposomes dependent on its ATPase activity and that LMBD1 exhibited no cobalamin transport activity. These results suggest that ABCD4 may be capable of transporting cobalamin from the lysosomal lumen to the cytosol. Furthermore, we examined a series of ABCD4 missense mutations to understand how these alterations impair cobalamin transport. Our findings give insight into the molecular mechanism of cobalamin transport by which ABCD4 involves and its importance in cobalamin deficiency.

Functional Analysis of the Transcriptional Regulator IκB-ζ in Intestinal Homeostasis.

BACKGROUND: The Toll-like receptor signaling pathway contributes to the regulation of intestinal homeostasis through interactions with commensal bacteria. Although the transcriptional regulator IκB-ζ can be induced by Toll-like receptor signaling, its role in intestinal homeostasis is still unclear. AIMS: To investigate the role of IκB-ζ in gut homeostasis. METHODS: DSS-administration induced colitis in control and IκB-ζ-deficient mice. The level of immunoglobulins in feces was detected by ELISA. The immunological population in lamina propria (LP) was analyzed by FACS. RESULTS: IκB-ζ-deficient mice showed severe inflammatory diseases with DSS administration in the gut. The level of IgM in the feces after DSS administration was less in IκB-ζ-deficient mice compared to control mice. Upon administration of DSS, IκB-ζ-deficient mice showed exaggerated intestinal inflammation (more IFN-g-producing CD4+ T cells in LP), and antibiotic treatment canceled this inflammatory phenotype. CONCLUSION: IκB-ζ plays a crucial role in maintaining homeostasis in the gut.

Detection of Characteristic Phosphatidylcholine Containing Very Long Chain Fatty Acids in Cerebrospinal Fluid from Patients with X-Linked Adrenoleukodystrophy.

X-linked Adrenoleukodystrophy (X-ALD) is a rare genetic neurological disorder caused by a mutation of the ABCD1 gene that encodes a peroxisomal ABC protein ABCD1. ABCD1 has a role in transporting very long chain fatty acid (VLCFA)-CoA into the peroxisome for ß-oxidation. ABCD1 dysfunction leads to reduced VLCFA ß-oxidation and in turn increased VLCFA levels in the plasma and the cells of all tissues; these increased plasma levels have been used to diagnose X-ALD. It has been reported that plasma VLCFA is not correlated with the severity and disease phenotype of X-ALD. Therefore, we cannot predict the disease progression by the plasma VLCFA level. Cerebrospinal fluid (CSF) is constantly produced by brain, and thus levels of lipids containing VLCFA in CSF might be informative in terms of assessing X-ALD pathology. LC-MS/MS-based analysis showed that phosphatidylcholine (PC) containing VLCFA signals, such as PC 40 : 0(24 : 0/16 : 0), PC 42 : 0(26 : 0/16 : 0), PC 44 : 4(24 : 0/20 : 4) and PC 46 : 4(26 : 0/20 : 4) were characteristically detected only in the CSF from patients with X- ALD. In the present study, we analyzed limited number of patient's CSF samples (2 patients with X-ALD) due to the limitations of the availability for CSF samples from this rare disease. However, our finding would offer helpful information for studying the disease progression biomarkers in X-ALD. To our knowledge, this is the first report of analyzing lipids containing VLCFA in CSF from patients with X-ALD.

OX40 Ligand-Mannose-Binding Lectin Fusion Protein Induces Potent OX40 Cosignaling in CD4+ T Cells.

OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is induced on activated T cells. Membrane-bound OX40 ligand (OX40L) expressed by activated antigen-presenting cells induces OX40 signaling, which promotes T cell immunity. OX40 agonism would be a potential target for immunotherapy, however, it remains unclear how the activity of OX40 can be successfully controlled by a designer OX40L protein. We prepared a soluble OX40L protein possessing a PA-peptide tag and a collagenous trimerization domain from mannose-binding lectin (MBL), and tested whether PA-MBL-OX40L fusion protein worked as an agonist for OX40. We found that the majority of recombinant PA-MBL-OX40L protein purified from culture supernatants displayed a trimer structure and bound to cell surface OX40 or OX40-Fc fusion protein in a dose-dependent manner. Upon stimulation of CD4+ T cells with TCR/CD3 without CD28, PA-MBL-OX40L displayed significantly increased proliferative and cytokine responses when compared with a benchmark agonistic monoclonal antibody for OX40. Both soluble and immobilized forms of PA-MBL-OX40L induced potent OX40 signaling in CD4+ T cells. Mice administered with PA-MBL-OX40L displayed significantly augmented T cell-mediated delayed-type hypersensitivity responses. Our results suggest that activity of OX40L could be engineered to elicit better T cell responses by rational design of its assembly and architecture.

IQ motif-containing GTPase-activating protein 1 is essential for the optimal maintenance of lung ILC2s.

Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 immunity and are crucial for pathogenesis of various types of inflammatory disease. IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein that is involved in multiple cellular functions such as cell survival and trafficking. While the roles for IQGAP1 in T and B lymphocytes have been uncovered, the physiological significance of IQGAP1 in innate lymphocytes remains to be elucidated. In the current study, we demonstrate that using bone marrow chimeras, the deficiency of IQGAP1 caused an impaired survival of lung ILC2s in a cell-intrinsic manner and that Iqgap1-/- mice displayed decreased accumulation of ILC2s after administration of papain and thereby reduced the pathology of the disease. Moreover, Iqgap1-/- ILC2s showed a significantly enhanced apoptosis as compared to wild-type ILC2s under both steady-state and inflammatory conditions. Together these results identify for the first time that IQGAP1 is essential for homeostasis of ILC2s in the lung.

Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome.

Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1ß, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1ß. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1ß for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.

IQGAP1 restrains T-cell cosignaling mediated by OX40.

A costimulatory signal from the tumor necrosis factor receptor (TNFR) family molecule OX40 (CD134), which is induced on activated T cells, is important for T-cell immunity. Aberrant OX40 cosignaling has been implicated in autoimmune and inflammatory disorders. However, the molecular mechanism by which the OX40 cosignaling regulates the T-cell response remains obscure. We found that OX40 associated with a scaffold protein, IQ motif-containing GTPase-activating protein 1 (IQGAP1) after ligation by its ligand OX40L. Naïve CD4+ T cells from Iqgap1-/- mice displayed enhanced proliferation and cytokine secretion upon receiving OX40 cosignaling. A C-terminal IQGAP1 region was responsible for its association with OX40, and TNFR-associated factor 2 (TRAF2) bridged these two proteins. The enhanced cytokine response in Iqgap1-/- T cells was restored by the expression of the C-terminal IQGAP1. Thus, the IQGAP1 binding limits the OX40 cosignaling. Disease severity of experimental autoimmune encephalomyelitis (EAE) was significantly exacerbated in Iqgap1-/- mice as compared to wild-type mice. Additionally, recipient mice with Iqgap1-/- donor CD4+ T cells exhibited significantly higher EAE scores than those with their wild-type counterparts, and OX40 blockade led to a significant reduction in the EAE severity. Thus, our study defines an important component of the OX40 cosignaling that restricts inflammation driven by antigen-activated T cells.

GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity.

Glucocorticoid-induced TNFR family related gene (GITR) is a member of the TNFR superfamily that is expressed on cells of the immune system. Although the protective and pathogenic roles of GITR in T cell immunity are well characterized, the role of GITR in innate immunity in the intestinal tissues has not been well clarified. In this study, using a dextran sulfate sodium (DSS)-induced colitis model in mice, we found that GITR-deficiency rendered mice more susceptible to acute intestinal inflammation and that a significantly higher number of activated natural killer (NK) cells was accumulated in the colonic lamina propria of Gitr-/- mice as compared to wild-type mice. Additionally, Rag2-/- Gitr-/- mice, which lack T cells but have NK cells, also displayed more severe colonic inflammation than Rag2-/- mice. In contrast, an anti-GITR agonistic antibody significantly alleviated colitis in Rag2-/- mice. Engagement of GITR inhibited IL-15-mediated activating signaling events in NK cells, which include cell activation and proliferation, and production of cytokines and cytotoxic granules. Taken together, our results provide the first evidence that GITR negatively controls intestinal inflammation through NK cell functions.

Bone marrow transplantation into Abcd1-deficient mice: Distribution of donor derived-cells and biological characterization of the brain of the recipient mice.

X-linked adrenoleukodystrophy (X-ALD) is a severe inherited metabolic disease with cerebral inflammatory demyelination and abnormal accumulation of very long chain fatty acid (VLCFA) in tissues, especially the brain. At present, bone marrow transplantation (BMT) at an early stage of the disease is the only effective treatment for halting disease progression, but the underlying mechanism of the treatment has remained unclear. Here, we transplanted GFP-expressing wild-type (WT) or Abcd1-deficient (KO) bone marrow cells into recipient KO mice, which enabled tracking of the donor GFP+ cells in the recipient mice. Both the WT and KO donor cells were equally distributed throughout the brain parenchyma, and displayed an Iba1-positive, GFAP- and Olig2-negative phenotype, indicating that most of the donor cells were engrafted as microglia-like cells. They constituted approximately 40% of the Iba1-positive cells. Unexpectedly, no decrease of VLCFA in the cerebrum was observed when WT bone marrow cells were transplanted into KO mice. Taken together, murine study suggests that bone marrow-derived microglia-like cells engrafted in the cerebrum of X-ALD patients suppress disease progression without evidently reducing the amount of VLCFA in the cerebrum.

TNF Receptor-Associated Factor 5 Limits Function of Plasmacytoid Dendritic Cells by Controlling IFN Regulatory Factor 5 Expression.

The physiological functions of TNF receptor-associated factor 5 (TRAF5) in the skin inflammation and wound healing process are not well characterized. We found that Traf5 -/- mice exhibited an accelerated skin wound healing as compared with wild-type counterparts. The augmented wound closure in Traf5 -/- mice was associated with a massive accumulation of plasmacytoid dendritic cells (pDCs) into skin wounds and an enhanced expression of genes related to wound repair at skin sites. In accordance with this result, adoptive transfer of Traf5 -/- pDCs, but not wild-type pDCs, into the injured skin area in wild-type recipient mice significantly promoted skin wound healing. The expression of skin-tropic chemokine receptor CXCR3 was significantly upregulated in Traf5-/- pDCs, and treatment with a CXCR3 inhibitor cancelled the promoted wound healing in Traf5-/- mice, suggesting a pivotal role of CXCR3 in pDC-dependent wound healing. Traf5 -/- pDCs displayed significantly higher expression of IFN regulatory factor 5 (IRF5), which correlated with greater induction of proinflammatory cytokine genes and CXCR3 protein after stimulation with TLR ligands. Consistently, transduction of exogeneous TRAF5 in Traf5-/- pDCs normalized the levels of abnormally elevated proinflammatory molecules, including IRF5 and CXCR3. Furthermore, knockdown of IRF5 also rescued the abnormal phenotypes of Traf5-/- pDCs. Therefore, the higher expression and induction of IRF5 in Traf5-/- pDCs causes proinflammatory and skin-tropic characteristics of the pDCs, which may accelerate skin wound healing responses. Collectively, our results uncover a novel role of TRAF5 in skin wound healing that is mediated by IRF5-dependent function of pDCs.

TRAF5 promotes plasmacytoid dendritic cell development from bone marrow progenitors.

The conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) originate from the same common dendritic cell precursor cells in the bone marrow. The pDCs produce large amounts of type 1 interferon in response to foreign nucleic acid and crucially contribute to host defense against viral infection. Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a pivotal component of various TNF receptor signaling pathways in the immune system. Although the functions of TRAF5 in T and B lymphocytes have been well studied, its roles in pDCs remains to be fully elucidated. In this study, we show that the expression of TRAF5 supports the generation of pDCs in the bone marrow and also critically contributes to the homeostasis of the pDC subset in the periphery in a cell-intrinsic manner. Furthermore, we provide evidence that TRAF5 promotes the commitment of DC precursor cells toward pDC versus cDC subsets, which is regulated by the balance of transcription factors TCF4 and ID2. Together our findings reveal that TRAF5 acts as a positive regulator of pDC differentiation from bone marrow progenitors.

Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells.

The costimulatory molecule 4-1BB and its ligand 4-1BBL can control adaptive immunity, but here we show that their interaction also suppressed myelopoiesis. We found that 4-1BBL was expressed on hematopoietic stem cells, differentiating common myeloid progenitors and granulocyte-macrophage progenitors, and 4-1BB was inducible on activated myeloid progenitors. Steady-state numbers of granulocyte-macrophage progenitors, myeloid-lineage cells and mature dendritic cells were higher in 4-1BB- and 4-1BBL-deficient mice, indicative of a negative function, and we confirmed that result with bone marrow chimeras and in vitro, where the absence of interactions between 4-1BB and 4-1BBL led to enhanced differentiation into dendritic cell lineages. The regulatory activity was mediated by 4-1BBL, with binding by 4-1BB inhibiting differentiation of myeloid progenitors. Thus, 4-1BB and 4-1BBL have a previously unknown function in limiting myelopoiesis and the development of dendritic cells.

TRAF2 and TRAF5 associated with the signal transducing receptor gp130 limit IL-6-driven transphosphorylation of JAK1 through the inhibition of proximal JAK-JAK interaction.

Tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF5 constitutively bind to glycoprotein 130 kDa (gp130) and inhibit IL-6-driven activation of signal transducer and activator of transcription 3 (STAT3) in CD4+ T cells, which limits the differentiation of pro-inflammatory IL-17-producing helper T cells that require IL-6-receptor (IL-6R) signals for their development. However, it is not known how the interaction between TRAF and gp130 negatively regulates STAT3 activity in the IL-6R complex. We hypothesized that TRAF proteins associated with gp130 might limit the activation of Janus kinase that is needed for the activation of STAT3. To test this, we transfected HEK293T cells to express gp130 and TRAF2 or TRAF5 together with two chimeric JAK1 proteins combined with either the N-terminal or the C-terminal protein fragment of firefly luciferase. Using this luciferase fragment complementation system, we found that the recovery of luciferase enzyme activity was coincident with proximal JAK1-JAK1 interaction and phosphorylation of JAK1 in the IL-6R complex and that the expression of TRAF protein significantly inhibited the recovery of luciferase activity. The binding of TRAF to gp130 via the C-terminal TRAF domain was essential for the inhibition. In accordance with this, upon stimulation of endogenous gp130 with a complex of IL-6 and IL-6R, Traf5-/- CD4+ T cells displayed significantly higher amounts of phosphorylated JAK1 than did their wild-type counterparts. Therefore, our results demonstrate that gp130-associated TRAF2 and TRAF5 inhibit the interaction between two JAK proteins in the IL-6R complex that is essential for initiating the JAK-STAT signaling pathway.

The TNF-TNFR Family of Co-signal Molecules.

Costimulatory signals initiated by the interaction between the tumor necrosis factor (TNF) ligand and cognate TNF receptor (TNFR) superfamilies promote clonal expansion, differentiation, and survival of antigen-primed CD4+ and CD8+ T cells and have a pivotal role in T-cell-mediated adaptive immunity and diseases. Accumulating evidence in recent years indicates that costimulatory signals via the subset of the TNFR superfamily molecules, OX40 (TNFRSF4), 4-1BB (TNFRSF9), CD27, DR3 (TNFRSF25), CD30 (TNFRSF8), GITR (TNFRSF18), TNFR2 (TNFRSF1B), and HVEM (TNFRSF14), which are constitutive or inducible on T cells, play important roles in protective immunity, inflammatory and autoimmune diseases, and tumor immunotherapy. In this chapter, we will summarize the findings of recent studies on these TNFR family of co-signaling molecules regarding their function at various stages of the T-cell response in the context of infection, inflammation, and cancer. We will also discuss how these TNFR co-signals are critical for immune regulation and have therapeutic potential for the treatment of T-cell-mediated diseases.

TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation.

Oncostatin M (OSM) is involved in pathogenesis of several human inflammatory diseases including lung inflammation and fibrosis. Although accumulating evidence indicates that OSM mediates lung inflammation, the precise mechanism for OSM on lung inflammation still remains unclear. In this study, we found that OSM receptor was abundantly expressed on endothelial and stromal/fibroblast cells in the lung of mice. In vitro stimulation with OSM upregulated vascular cell adhesion molecule-1 (VCAM-1), which promotes eosinophil infiltration in the lung tissues, on freshly-isolated lung stromal/fibroblast cells from wild-type mice. However, these cells from TNF receptor associated factor 5 (TRAF5)-deficient mice failed to show the increase in VCAM-1 expression after OSM stimulation. Furthermore, Traf5-/- mice showed markedly attenuated lung inflammation in terms of eosinophil infiltration upon intranasal administration with OSM as compared to wild-type mice. These results indicate that TRAF5 is crucially involved in OSM-mediated lung inflammation probably by inducing lung stromal/fibroblast cell activation.