Abstract
This Special Edition of Cytokines and Growth Factor Reviews emerged from the most recent International TNF Conference, held May 13–16, 2007. The conference, organized by TNF aficionados, Avi Ashkenazi (Genentech, South San Francisco) and Jeffrey Browning (BiogenIDEC, Boston, MA), was held a second time in the serene coastal environs of the rustic Asilomar State Conference Center in Monterey, California. The scientific presentations at the Asilomar meeting kept pace with the previous 10 pseudo biennial TNF-related cytokine conferences, each heralding new discoveries about this important family of cytokines. Perhaps as a sign of the family’s maturing knowledge base, new results from clinical trials were revealed for members of the family other than TNF, such as TRAIL in cancer and Lymphotoxin-β in rheumatoid arthritis. The next meeting, the 12th International TNF Conference is scheduled for April 26–29, 2009 in El Escorial, Madrid, Spain, co-chaired by Marc Feldman and David Wallach (www.tnf2009.org).
Cytokines and Growth Factor Reviews Editor John Hiscott requested (in his ever cogent fashion) an update on the TNF Superfamily. The previous CGFR TNF Superfamily special edition in 2003 reflected the meeting held in 2002 in San Diego in which I also served as guest editor [1]. With passage of just five years, we thought the burning questions of the time were addressed, however the 2007 Conference revealed unanticipated features of the TNF Superfamily in all aspects of physiology and development.
The knowledge-base of the TNF Superfamily in 2008 is huge, so large that an attempt to comprehensively cover all aspects of the TNF Superfamily in print risks accelerating global warming. The popularity of TNF is unmatched by any other cytokine. Pubmed various cytokines, TNFα comes up as the big hit at 8×104 citations, next in line is IL-2 (4.6×104), IL-1(4.3×104), IFNα (2.7×104) and CD40 drops in at 8×103 citations. In an attempt to cover the breadth of new advances in the field, this special edition of CGFR represents an eclectic ensemble of lectures presented at the meeting. I offered the authors the freedom to expand their lectures to include review the their recent work. Due to the limited format, my deep apologies to the many deserving scientists that I was unable to incorporate into this edition.
The portrait of all the ligands and receptors in the TNF Superfamily is large and complicated (Table 1)(see also [2] for binding interactions), yet accessing the structure and genetic features has never been easier due to so many excellent databases, including the official genome nomenclature site (www.genenames.org), which introduced the TNFSF and TNFRSF numbering system.
Table 1.
| Table 1a | TNF SuperFamily-chromosomal locations | ||||
|---|---|---|---|---|---|
| chromosomal location | mRNA accession numbers | ||||
| gene name/alias | human | mouse | human | mouse | Ligand symbol |
| TNF | 6p21.3 | ch17 (19.06 cm) | NM_000594 | NM_013693 | TNFSF1A |
| LTα | 6p21.3 | ch17 (19.06 cm) | NM_000595 | NM_010735 | TNFSF1B |
| LTβ | 6p21.3 | ch17 (19.06 cm) | NM_002341 | NM_008518 | TNFSF3 |
| OX40-L | 1q25 | ch1 (84.90 cM) | NM_003326 | NM_009452 | TNFSF4 |
| CD40-L, CD154 | Xq26 | chX (18.0 cM) | NM_000074 | NM_011616 | TNFSF5 |
| Fas-L | 1q23 | ch1 (85.0 cM) | NM_000639 | NM_010177 | TNFSF6 |
| CD27-L, CD70 | 19p13 | ch17 (20.0 cM) | NM_001252 | NM_011617 | TNFSF7 |
| CD30-L, CD153 | 9q33 | ch4 (32.20 cM) | NM_001244 | NM_009403 | TNFSF8 |
| 4-1BB-L | 19p13 | ch17 (20.0 cM) | NM_003811 | NM_009404 | TNFSF9 |
| TRAIL | 3q26 | ch3 | NM_003810 | NM_009425 | TNFSF10 |
| RANK-L, TRANCE | 13q14 | ch14 (45.0 cM) | NM_003701 | NM_011613 | TNFSF11 |
| TWEAK | 17p13 | ch11 | NM_003809 | AF030100 | TNFSF12 |
| APRIL/TALL2 | 17P13.1 | ch13 | NM_003808 | NM_023517 | TNFSF13 |
| BAFF, BLYS, TALL1 | 13q32–q34 | ch8 (3cM) | NM_006573 | NM_033622 | TNFSF13B |
| LIGHT | 19p13.3 | ch17 (D-E1) | NM_003807 | NM_019418 | TNFSF14 |
| TL1A | 9q33 | ch4 (31.80cM) | NM_005118 | AF520786 | TNFSF15 |
| GITRL, AITRL | 1q23 | unknown | NM_005092 | unknown | TNFSF18 |
| EDA1 | Xq12–q13.1 | chX (37.0 cM) | NM_001399 | NM_010099 | |
| EDA2 | Xq12–q13.1 | chX (37.0 cM) | AF061189 | AJ243657 | |
| Table 1b | TNF Receptor SuperFamily | ||||
|---|---|---|---|---|---|
| chromosomal location | mRNA accession numbers | ||||
| Gene name/aliases | human | mouse | human | mouse | Gene Symbol |
| TNFR-1, p55–60 | 12p13.2 | ch6 (60.55cM) | NM_001065 | NM_011609 | TNFRSF1A |
| TNFR2, p75–80 | 1p36.3-36.2 | ch4 (75.5cM) | NM_001066 | NM_011610 | TNFRSF1B |
| LTβR | 12p13 | ch6 (60.4cM) | NM_002342 | NM_010736 | TNFRSF3 |
| OX40 | 1p36 | ch4 (79.4cM) | NM_003327 | NM_011659 | TNFRSF4 |
| CD40 | 20q12–q13.2 | ch2 (97.0cM) | NM_001250 | NM_011611 | TNFRSF5 |
| FAS, CD95 | 10q24.1 | ch19 (23.0cM) | NM_000043 | NM_007987 | TNFRSF6 |
| DcR3 | 20q13 | unknown | NM_003823 | unknown | TNFRSF6B |
| CD27 | 12p13 | ch6 (60.35) | NM_001242 | L24495 | TNFRSF7 |
| CD30 | 1p36 | ch4 (75.5cM) | NM_001243 | NM_009401 | TNFRSF8 |
| 4-1BB | 1p36 | ch4 (75.5cM) | NM_001561 | NM_011612 | TNFRSF9 |
| TRAILR-1, DR4 | 8p21 | unknown | NM_003844 | unknown | TNFRSF10A |
| TRAIL-R2, DR5 | 8p22-p21 | ch14 (D1) | NM_003842 | NM_020275 | TNFRSF10B |
| TRAILR3, DcR1 | 8p22-p21 | ch7 (69.6cM) | NM_003841 | NM_024290 | TNFRSF10C |
| TRAILR4, DcR2 | 8p21 | ch7 (69.6cM) | NM_003840 | NM_023680 | TNFRSF10D |
| RANK, TRANCE-R | 18q22.1 | ch1 | NM_003839 | NM_009399 | TNFRSF11A |
| OPG, TR1 | 8q24 | ch15 | NM_002546 | NM_008764 | TNFRSF11B |
| FN14 | 16p13.3 | ch17 | NM_016639 | NM_013749 | TNFRSF12A |
| TRAMP, DR3, LARD | 1p36.3 | ch4 (E1) | NM_003790 | NM_033042 | TNFRSF25 |
| TACI | 17p11.2 | ch11 | NM_012452 | NM_021349 | TNFRSF13B |
| BAFFR | 22q13.1–q13.31 | ch15 | NM_052945 | NM_028075 | TNFRSF13C |
| HVEM, HveA, ATAR | 1p36.3–p36.2 | ch4 | NM_003820 | NM_178931.2 | TNFRSF14 |
| p75NTR, NGFR | 17q12–q22 | ch11 (55.6cM) | NM_002507 | NM_033217 | TNFRSF16 |
| BCMA | 16p13.1 | ch16 (B3) | NM_001192 | NM_011608 | TNFRSF17 |
| AITR, GITR | 1p36.3 | ch4 (E) | NM_004195 | NM_009400 | TNFRSF18 |
| RELT | 11q13.2 | unknown | NM_152222 | unknown | TNFRSF19L |
| TROY, TAJ | 13q12.11–q12.3 | ch14 | NM_018647 | NM_013869 | TNFRSF19 |
| EDAR | 2q11–q13 | ch10 | NM_022336 | NM_010100 | |
| DR6 | 6P12.2–21.1 | ch17 | NM_014452 | NM_052975 | TNFRSF21 |
| EDA2R | Xq11.1 | unknown | NM_021783 | unknown | |
| mTNFRH3 | unknown | ch7(69.9cM) | unknown | NM_175649 | |
The deep penetrance of the TNF Superfamily into many physiological processes [3] brings the realization that pigeonholing any one ligand-receptor pair to a discrete physiologic compartment denies the reality of the functional diversity each ‘system”. Hence, I loosely organized this volume into four themes: i. Regulating differentiation and survival, ii. Organogenesis and regeneration, iii. CoSignaling in homeostasis and Immune responses, and iv. Mechanisms of inflammation and apoptosis.
i. Regulating differentiation and survival
All of the cellular TNF receptors (aside from the decoy receptors) retain the conserved function of activating the family of nuclear factors of κB. NFκB controls many genes that regulate cellular differentiation, survival and death (for an updated list go to: www.nf-kb.org), which determine much of the core functions of the TNFR signaling systems. Soumen Basak and Alex Hoffmann (UCSD) discuss the intrinsic and extrinsic dynamics of the family of κB transcription factors, revealing common and unique steps in κB activation by TNFR and LTβR. The TNF receptor associated factors (TRAF) are cytoplasmic adaptors that provide the crucial intracellular link between ligated receptors and activation of NFκB and other intracellular signaling pathways. Gail Bishop and colleagues (University of Iowa) review the TRAF family with a focus their role in B cells. David Wallach and associates (Weizmann Institute of Science) focus on Caspase 8 in its well known role as death mediator, but as a lesson for aspiring prophets, reveals the unexpected non-cell autonomous impact of caspase 8 inhibition.
ii. Organogenesis and regeneration
Gene mutations in humans and mice often have profound impact on development programs required for nervous system, skin and lymphoid tissues. One of the most dramatic and observable phenotypes in mice impacts the ectoderm. The developmental blueprint of the ectoderm as controlled by the Ectodysplasin (EDA) system is reviewed by Marja Mikkola (University of Helsinki), revealing new insights into this model developmental program. Surprisingly, other members of the TNF superfamily such as Rank ligand, lymphotoxins, and TNF impact specific aspects of skin appendage biology, including branching of the mammary gland, hair shaft formation, and hair follicle cycling. Sergei Nedospasov and team of geneticists (Engelhardt Institute of Molecular Biology and German Rheumatism Research Centre) review the extraordinary studies aimed at understanding the molecular physiologic functions of TNF using transgenic and knockout models. No less than 20 distinct gene variants constructed to analyze TNF expression, regulation and pathogenesis, reveal the incredible depth of understanding we now have for a mechanism of action of this cytokine. Sha Mi (BiogenIDEC) discusses the exciting discovery that the orphan TNF receptor, known as TROY (or Taj) is critical for axon growth and regeneration. Indeed, TROY is more specifically expressed in postnatal and adult neurons than nerve growth factor receptor p75. TROY associates with Nogo receptor 1, functionally replacing in the p75/NgR1/LINGO-1 complex. A new look for a founding member of this receptor superfamily.
iii. CoSignaling in homeostasis and Immune responses
A large cluster of TNFR in human reside on Chr 1p36, and their TNF ligands are clustered in regions of the genome paralogous to the MHC on Chr 6 with TNF, LTα, and LTβ [4]. The TNFR homologs, TNFR2, HVEM, Ox40, 41BB, CD30, GITR and DR3 share cosignaling activity in directing the complex differentiation of T cells. Michael Croft and colleagues (La Jolla Institute for Allergy and Immunology) describe their work on OX40 (CD134) and 4-1BB (CD137) as costimulatory receptors for both CD4 and CD8 T cell proliferation, survival, and cytokine production. Croft proposes a role of these costimulatory TNFR in the function of regulatory T cells to explain unexpected properties of Ox40 and 41BB. What T cells have, B lymphocytes more than make up for it in the complicated biology associated with BAFF (B cell activating factor of the TNF Family). With three distinct receptors and shared ligands the BAFF APRIL family rivals TNF and LT. Fabienne Mackay (The Garvan Institute of Medical Research) and Pascal Schneider (University of Lausanne) look closely at the BAFF receptor, TACI. TACI−/− mice revealed two sides to this receptor, a positive one driving T cell-independent immune responses, and a negative side, down-regulating B cell activation and expansion. Two sides to a TNFR is an emerging theme. The herpesvirus entry mediator (HVEM) binds two ligands on opposite sides of the molecule [5]. HVEM binds LIGHT, a ligand related to LTβ, and BTLA, (B and T lymphocyte attenuator), an Immunoglobulin family member with inhibitory signaling properties [6, 7]. My associate, Carl De Trez (Université Libre de Bruxelles), discusses results revealing the HVEM-BTLA pathway provides inhibitory signaling to dendritic cells, which counter acts the trophic action of LTβR signaling necessary for the local proliferation of DC in lymphoid tissues [8]. Yang-Xin Fu and colleagues (University of Chicago) highLIGHT the anti-tumor properties of Lymphotoxin-related ligand, LIGHT. LIGHT conditions the tumor microenvironment in a sufficiently robust fashion to drive CD8 T cell differentiation into cytotoxic effectors that can eradicate metastases. The work implicates LIGHT as promising candidate for an effective cancer immunotherapy.
iv. Mechanisms of inflammation and apoptosis
In what was one of the most illuminating lectures Shigekazu Nagata revealed a molecular pathway linking apoptosis, DNA degradation with IFN and TNF production to a autoimmune like syndrome, chronic polyarthritis. Basic research on apoptotic pathways revealed a defect in lysosomal DNA degradation activates macrophages to produce cytokines such as IFNβ and TNF in a Toll-like receptor (TLR)-independent manner. IFNβ expressed in the fetal mouse induces apoptosis of erythroid and lymphoid precursor cells, with fatal results. However, loss of DNAse II after birth leads to chronic TNF production causing chronic polyarthritis that resembles human rheumatoid arthritis. Sun-Mi Park and Marcus Peter explore micro RNAs, discovering a new mechanism of regulating apoptosis through Fas/CD95 signaling pathway involving miRNAs as regulators of death receptor signaling. Many conventional therapies for cancer fail because mutational inactivation of the p53 tumor-suppressor gene, which regulates apoptosis via the cell-intrinsic pathway, reduces sensitivity to chemotherapy. Avi Askenazi (Genentech) reports on exploiting the cell extrinsic apoptotic pathway using two agonists of the death receptors for TRAIL. In contrast to TNF, the initial data on recombinant TRAIL and an agonist monoclonal antibody to TRAIL death receptors, Apomab, in safety trials confirm that these agents are suitable for further clinical investigation as cancer therapeutics. TNFR signaling rapidly activates cellular death and survival pathways within minutes, and the regulatory brakes must parallel this speed. Ubiquitination delivers a rapid posttranslational mechanism covalently modifying proteins and for controlling protein abundance. The first ubiquitinylated derivative identified in the signaling cascade was Inhibitor of NF-κB. Ingrid E. Wertz and Vishva M. Dixit (Genentech) show that nearly every step of TNFR1 signaling is regulated by ubiquitination.
This issue of CGFR provides a close examination of several individual members of the TNF Superfamily and as a collective volume the hope is to provide the reader with a cross section of the TNF superfamily revealing the integrated nature of these cellular communication systems common to the entire family.
Footnotes
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