The TNF receptor super family in immune regulation

This article is part of a series of reviews covering TNF Receptor Family Members appearing in Volume 244 of Immunological Reviews. This volume of Immunological Reviews is focused on the cytokines related to tumor necrosis factor (TNF). Based on structural homology, the TNF-related cytokines form a superfamily (TNFSF) of proteins that engage specific cognate cell surface receptors, the TNF receptor superfamily (TNFRSF) (reviewed in 1) (Fig. 1). Special attention to this specific cytokine family is due to the importance of these molecules in immune function and human disease. The successful treatment of some human autoimmune diseases such as rheumatoid arthritis with TNF inhibitors provides a proven experimental basis for developing antibody and receptor-based biologic therapeutics targeted at TNF (2). No fewer than five approved drugs targeting TNF are in the clinic. Clinical experiences with these inhibitors, each with subtle, but distinct mechanisms, are providing insight into the biology of human disease only hinted at in animal models. However, some patients fail to respond to TNF blockade, revealing a lack of predictive knowledge concerning this cytokine family (3). The aspiration of current research is to place the molecular features of these cytokines into a physiologic context that enhances our understanding of the clinical outcomes. Ligand-receptor interactions in the TNF superfamily. The human chromosomal position of the ligands are shown above the red line, and the arrows are drawn pointing toward their specific cognate receptors. The brown and purple lines represent membranes to which the ligands and receptors attach. The TNF-related cytokines form a superfamily, members are shown as trimers, ligands for NGF and BTLA/CD160 are Ig superfamily members (shown as dimmers), and TNFRSF members are shown as linked ovals each representing a cysteine-rich domain. The individual ligand-receptor systems within these two superfamilies are connected in both the extracellular and intracellular spaces to form networks of signaling pathways. These networks allow lymphocytes to communicate with each other, and with cells in their surrounding microenvironment and at a distance. There is also significant interconnectedness between the individual ligand-receptor systems, with shared ligands and receptors, that add complexity not redundancy to the network [e.g. lymphotoxin-αβ and LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed on T lymphocytes) systems]. Further, the defining structural motifs in the extracellular domains of TNFSF and TNFRSF can connect with other protein families, for example the immunoglobulin superfamily [e.g. herpes virus entry mediator (HVEM) and B and T lymphocyte attenuator (BTLA)], a feature significantly expanding the connectivity of the TNFSF communication network. The signaling networks created by the members of TNF-TNFR superfamily reach into nearly all physiologic processes including neuronal, ectodermal, and immune systems. The involvement of TNF members in so many aspects of biology circumvents a review of each ligand-receptor pair. Here, I selected scientists with new results focused on components of signaling pathways in specific cell types or immune disease models that may provide insight into targeting these pathways for drug development. The activation of signaling pathways occurs through a common mechanism of receptor clustering embedded in the TNF ligand’s conserved trimeric structure. Receptor clustering in the responding cell provides the conformational alteration that initiates signaling through adapter molecules that themselves assembly unique enzymatically active signaling complexes. Although the receptors have no intrinsic enzymatic activity, they recruit adapters that link to enzymes. These receptor-adapter signaling complexes initiate activation of proteases, ubiquitin ligases, kinases, and phosphatases (not all at once!) that regulate pathways leading to cellular differentiation, survival, or death. Immortalized cancer cells frequently harbor mutations in the pathways regulating nuclear factor κB (NFκB) activation (4). Receptor-initiated pathways activate a common set of transcription factors, and the NFκB family is the most intensely studied because of direct regulation of genes controlling cell death and survival. Yet, each ligand-receptor pair displays a unique physiologic phenotype, often challenging the predictive capability of our signaling paradigms. In this series, I selected scientists leading our understanding of the signaling pathways initiated by TNFRSF. Henning Walczak (5) provides a detailed examination of the functional importance of the different modes of ubiquitination that are so critical in controlling the activities of the type 1 TNFR, the primary proinflammatory receptor. The common target of TNFR signaling is activation of NFκB family of transcriptional regulators. The signals emanating from the TNFR impinge on a few key serine kinases that activate different members of the NFκB family. Bärbel Schröfelbauer and Alexander Hoffman (6) address the specificity of target gene activation from a limited number kinases required for NFκB activation. Genhong Cheng and colleagues (7) specifically address the regulation of the NFκB-inducing kinase NIK, the key serine kinase involved in the noncanonical pathway, and its mechanisms of regulating gene expression. Gail Bishop and her laboratory members (8) provide their understanding of the TNF-receptor associated factor (TRAF) family as key adapters linking the ligated TNFR to downstream signaling cascades. The TRAF3 adapter is particularly important in controlling the NIK-NFκB pathway through ubiquitin-dependent mechanisms by all TNFRs. However, the TRAF family is also essential for the function of innate pathogen sensors (e.g. Toll-like receptors and Cardiff) that control type 1 interferons, thus the TRAF family links the innate signaling pathways with the TNFR controlled systems into supra-networks. Lymphoid tissues are the sites where immune reactions initiate. Lymph nodes undergo dynamic changes, where multiple cellular interactions occur between stromal cells forming the microarchitecture of the organ, antigen-presenting dendritic cells, and the antigen-reactive B cells and T cells that initiate immune responses. Lymph nodes undergo dramatic remodeling during and after an immune response with dynamic regulation of lymph and blood flow and altered cellular trafficking. Mingzhao Zhu and Yang-Xin Fu (9) examine how the flow of lymph and blood and cell trafficking through lymph nodes is regulated by the lymphotoxin-αβ signaling system. Jennifer Gommerman and Leslie Summers deLuca (10) reveal that the regulation of key cytokine secretion by dendritic cells is differentially regulated by CD40 and LTβ receptor pathways, thus indirectly modulating the CD8+ T-cell responses. The LTβR has stood as one of the key stromal cell regulating TNFRSF members; however, the TWEAK-Fn14 system, discussed by Linda Burkly et al. (11), initiates a wide range differentiation signals in tissue parenchymal and stromal cells. Strikingly, the duration of signaling by Fn14 is beneficial when transient, but becomes pathogenic under sustained conditions. The biology of B-cell activating factor belonging to the TNF family (BAFF) clearly centers on the differentiation of B cells, yet the complexity of the BAFF-a proliferation-inducing ligand (APRIL) system, perhaps rivaling the LTαβ-LIGHT system, suggests additional complex controls governing B-cell behavior. Robert Rickert and his research fellows (12) clarify the complexities in the BAFF-APRIL system helping to facilitate the understanding of B-cell malignancies and autoimmune diseases. The differentiation of T cells into effector and memory cells depends on TCR engagement that coincides with additional cooperating signaling receptors in the immunoglobulin and TNFRSF (13). The genes of several of the TNFRSF cosignaling receptors important in T-cell function reside on Chr 1p36. The cosignaling TNFR include OX40, 41BB, HVEM, TNFR2, glucocorticoid induced TNFR (GITR), and DR3. The review from Peter Lane’s laboratory (14) addresses the role of OX40 and CD30 signals in CD4+ T-cell effector and memory function. Here, the discussion considers the rare, innate lymphocyte-like cell, also known as the lymphoid tissue inducer cell, in its role in the maintenance of memory T cells. The OX40 also plays an essential role in CD8+ T cells required for host defense. Shahram Salek-Ardakani (15) brings to our attention the non-redundant functions of OX40 as a cosignaling molecule for CD8+ T cells in models of viral infection in the lung and the potential to exploit this system in vaccine development. Building on the importance of TNFRSF cosignaling molecules as non-redundant pathways for effector and memory T-cell differentiation, Marcos Steinberg, Timothy Cheung, and I (16) delve into the regulatory roles, both positive and inhibitory, played by HVEM in T-cell survival. These critical non-redundant roles for HVEM and its ligands are revealed in T-cell driven inflammation in the lung and intestines. Richard Siegel and colleagues (17) describe recent results examining the TL1A-DR3 system in mouse disease models. The DR3 is a paralog of TNFR1 utilizing the death domain and the adapter TNFR-associated death domain protein to initiate signaling. Persistent activation of TL1A-DR3 system induces intestinal inflammatory response dependent on interleukin-13 that is associated with allergic and anti-parasitic responses. These studies suggest that TL1A may be a viable target. Tania Watts and associates (18) review recent results examining TNFRSF members 41BB and GITR as non-redundant cosignaling molecules in severe influenza model. The effector T-cell enhancing effects of 41BB and OX40 have prompted the use of antibody agonists to enhance T-cell responses to cancer. Unfortunately, the 41BB agonist proved toxic; however, 41BB reengineered into effector T cells along with an antibody signaling system destroyed drug resistant B-lymphoma (19). Andrew Weinberg (20) provides a personal account of the efforts to advance cancer therapy with agonists of OX40. Exploitation of TNFR superfamily in human cancer therapy is increasing. As a recent example, the prominent expression of CD30 on lymphoma cells (originally discovered as the Ki antigen on malignant B cells in Hodgkin’s lymphoma) was exploited as a conjugate of an anti-CD30 antibody with the tubulin chemotherapy drug auristatin (brentuximab vedotin). The recent approval of this CD30-based drug for relapsing/recurrent Hodgkin’s lymphoma defines another translational milestone for the TNFRSF (21, 22). In 2011, a clearer understanding of the molecular details and pathways of the TNFRSF are emerging with the hope of providing new strategies for disease intervention. This volume focuses on the TNFRSF in immune function reflecting some practical limitations and my own bias. I have also attempted to provide a stage for some of the newer voices working in the TNF field, which I believe herald the vitality of research in this area. In this regard, the International TNF conference, now in its 3rd decade, was recently held at Awaji, Japan not long after the devastating earthquake and tsunami. Chaired by Shigekazu Nagata and Masayuki Miura, the conference successfully brought forth new findings, some presented in this series of articles. Quebec City, Canada will provide the venue for the 14th TNF Conference, July 7–10, 2013, chaired by Linda Burkly and Jennifer Gommerman (http://www.tnf2013.com). More exciting discoveries are surely on the horizon. On behalf of all TNF researchers, this volume is dedicated to Jurg Tschopp. The author declares no conflict of interest.

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