The TNF Superfamily

Cytokine & Growth Factor Reviews 14 (2003) 181–184

Introduction

The TNF Superfamily The Tumor Necrosis Factor (TNF) superfamily of cytokines activate signaling pathways for cell survival, death, and differentiation that orchestrate the development, organization and homeostasis of lymphoid, mammary, neuronal and ectodermal tissues. This special edition of Cytokine & Growth Factor Reviews is devoted to recent advances in this diverse family. Members of the TNF family of membrane-bound and secreted ligands pair off with one or more specific cell surface receptors that form a corresponding family of cognate receptors (TNFR). Each ligand–receptor pair is considered a system, and now over 40 distinct ligand–receptor systems (with more on the horizon) are currently recognized. Indeed, the size of the family has grown such that a portrait of the family must be presented as a composite (Fig. 1A and B). The active investigation of these cytokines has created a nomenclature nightmare, although introduction of a numerical system to help standardize gene names (http://www.gene.ucl.ac.uk/nomenclature/) will help, especially in tracking TNF genes in the genome. Nonetheless, the use of more common, and often colorful, acronyms continues. The name, rank and genomic serial number of each ligand (Table 1) and receptor (Table 2) is tabulated along with additional pertinent information for human and mouse genes. TNF and lymphotoxin (LT) the prototypic members of the family have well-established functions that have driven their entry into the clinical arena as their specific inhibitors are proving useful in blocking inflammation in autoimmune diseases such as rheumatoid arthritis. The functions of several other systems are emerging, whereas some newer members are less well defined or are orphans. No doubt as knowledge accumulates, therapeutic modulation of some of these systems will have significant impact on human disease. A number of branches in the TNF family tree are now recognized. The sequence and structural homology in the ectodomain of the ligands and receptors defines the families. The key feature in the receptors is a cysteine-rich domain (CRD) formed of three disulfide bonds surrounding a core motif of CXXCXXC creating an elongated molecule. Significant variation in the number of CRD occurs among family members, from BAFFR with only a partial CDR and to six in CD30. Although the low affinity nerve growth factor receptor (NGFR) has the classic CRD structure, it binds

the structurally distinct neurotrophins. Another divergence of the TNFR family is found in herpesvirus and poxvirus, which contain orthologs captured from the cellular genome. The TNF-related ligands are type II (intracellular N-terminus) transmembrane proteins containing a ‘TNF homology domain’ (THD) at the extracellular C terminus. The THD folds into an antiparallel ␤-sandwich that assembles into trimers and thus each ligand has three receptor binding sites, formed as a groove between adjacent subunits. Receptor clustering induced by the multivalent ligand forms the basic paradigm of signal transduction. The THD and trimeric configuration is also found in the complement C1q globular domain, which represents a significant branch in the TNF family tree. At least seven additional C1q-like proteins with this TNF homology domain are present in the genome; it is not known if these engage TNF receptors. Clearly, an area to watch develop in the coming years. Together these branches in the family reveal the adaptability of the THD and CRD structures allowing connections to diverse signaling pathways that initiate appropriate cellular responses. The significant cross utilization of ligands or receptors observed in the different systems suggests the signaling pathways are highly integrative. Indeed, it was previously felt that common use of receptors indicated redundancy, but in this family each system appears to have a unique function. In part, the unique biology is derived from distinct signaling pathways activated by these cytokine systems. This conclusion is supported by genetic approaches to define the physiological functions linked to individual components. Pfeffer (chapter 1) discusses the elucidation of the biological functions of the immediate TNF-related cytokines and their specific cell surface receptors through the study of gene-targeted mouse strains in infection, sepsis and autoimmunity. In most cases, mice with targeted deletions have complex phenotypes, and it has taken a significant effort to link genotype with phenotype; some remain undefined. A common theme that emerges from the TNF superfamily is the ability of these signal initiation systems to regulate cell death and survival pathways, which underlies at some level many of the gross phenotypes linked to the various systems. To assist the reader in establishing a more complete understanding of fundamental aspects of the TNF superfamily, Cheng and coworkers (chapter 2) review

1359-6101/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1359-6101(03)00032-7

182

Introduction / Cytokine & Growth Factor Reviews 14 (2003) 181–184

Fig. 1. The TNF superfamily in 2003. Depiction of the TNF-related ligands as membrane-anchored trimers arranged according to their chromomsomal positions (upper panel). Arrows indicate interactions with receptor where known. The ectodomain of the receptors shown in blue and approximate the number of CRD. Those receptors with cytoplasmic tails that contain a death domain are identified with a yellow cylinder; the other receptors bind TRAF adaptors, which lead to signal transduction pathways for apoptosis or cell survival: (A) TNF and related ligands encoded in the MHC (chromosome 6) and paralogous regions on chromosomes 1, 9 and 19 and their receptors; (B) other ligands and receptors in the TNF superfamily.

Introduction / Cytokine & Growth Factor Reviews 14 (2003) 181–184

183

Table 1 TNF superfamily—chromosomal locations Gene name/alias

TNF LT␣ LT␤ OX40-L CD40-L, CD154 Fas-L CD27-L, CD70 CD30-L, CD153 4-1BB-L TRAIL RANK-L, TRANCE TWEAK APRIL/TALL2 BAFF, BLYS, TALL1 LIGHT TL1A GITRL, AITRL EDA1 EDA2

Chromosomal location

mRNA accession numbers

Ligand symbol

Human

Mouse

Human

Mouse

6p21.3 6p21.3 6p21.3 1q25 Xq26 1q23 19p13 9q33 19p13 3q26 13q14 17p13 17p13.1 13q32–q34 19p13.3 9q33 1q23 Xq12–q13.1 Xq12–q13.1

Ch17 (19.06 cM) Ch17 (19.06 cM) Ch17 (19.06 cM) Ch1 (84.90 cM) ChX (18.0 cM) Ch1 (85.0 cM) Ch17 (20.0 cM) Ch4 (32.20 cM) Ch17 (20.0 cM) Ch3 Ch14 (45.0 cM) Ch11 Ch13 Ch8 (3 cM) Ch17 (D-E1) Ch4 (31.80 cM) Unknown ChX (37.0 cM) ChX (37.0 cM)

NM 000594 NM 000595 NM 002341 NM 003326 NM 000074 NM 000639 NM 001252 NM 001244 NM 003811 NM 003810 NM 003701 NM 003809 NM 003808 NM 006573 NM 003807 NM 005118 NM 005092 NM 001399 AF061189

NM 013693 NM 010735 NM 008518 NM 009452 NM 011616 NM 010177 NM 011617 NM 009403 NM 009404 NM 009425 NM 011613 AF030100 NM 023517 NM 033622 NM 019418 AF520786 Unknown NM 010099 AJ243657

TNFSF1A TNFSF1B TNFSF3 TNFSF4 TNFSF5 TNFSF6 TNFSF7 TNFSF8 TNFSF9 TNFSF10 TNFSF11 TNFSF12 TNFSF13 TNFSF13B TNFSF14 TNFSF15 TNFSF18

Unigene Human

Mouse

Hs.241570 Hs.36 Hs.890 Hs.181097 Hs.652 Hs.2007 Hs.99899 Hs.1313 Hs.1524 Hs.83429 Hs.115770 Hs.26401 Hs.54673 Hs.270737 Hs.129708 Hs.241382 Hs.248197 Hs.105407 Unknown

Mm.1293 Mm.87787 Mm.1715 Mm.4994 Mm.4861 Mm.3355 Mm.42228 Mm.466 Mm.41171 Mm.1062 Mm.6426 Mm.8983 Mm.54359 Mm.28835 Mm.103577 Unknown Unknown Mm.6258 Unknown

Table 2 TNF receptor superfamily—chromosomal locations Gene name/aliases

TNFR-1, p55–60 TNFR2, p75–80 LT␤R OX40 CD40 FAS, CD95 DcR3 CD27 CD30 4-1BB TRAILR1, DR4 TRAILR2, DR5 TRAILR3, DcR1 TRAILR4, DcR2 RANK, TRANCE-R OPG, TR1 FN14 TRAMP, DR3, LARD TACI BAFFR HVEM, HveA, ATAR p75NTR, NGFR BCMA AITR, GITR RELT TROY, TAJ EDAR DR6 XEDAR mTNFRH3

Chromosomal location

mRNA accession numbers

Human

Mouse

Human

Mouse

Gene symbol

Human unigene

Mouse unigene

12p13.2 1p36.3-36.2 12p13 1p36 20q12–q13.2 10q24.1 20q13 12p13 1p36 1p36 8p21 8p22–p21 8p22–p21 8p21 18q22.1 8q24 16p13.3 1p36.3 17p11.2 22q13.1–q13.31 1p36.3–p36.2 17q12–q22 16p13.1 1p36.3 11q13.2 13q12.11–q12.3 2q11–q13 6p12.2–p21.1 Xq11.1 Unknown

Ch6 (60.55 cM) Ch4 (75.5 cM) Ch6 (60.4 cM) Ch4 (79.4 cM) Ch2 (97.0 cM) Ch19 (23.0 cM) Unknown Ch6 (60.35) Ch4 (75.5 cM) Ch4 (75.5 cM) Unknown Ch14 (D1) Ch7 (69.6 cM) Ch7 (69.6 cM) Ch1 Ch15 Ch17 Ch4 (E1) Ch11 Ch15 Ch4 Ch11 (55.6 cM) Ch16 (B3) Ch4 (E) Unknown Ch14 Ch10 Ch17 Unknown Ch7 (69.9 cM)

NM 001065 NM 001066 NM 002342 NM 003327 NM 001250 NM 000043 NM 003823 NM 001242 NM 001243 NM 001561 NM 003844 NM 003842 NM 003841 NM 003840 NM 003839 NM 002546 NM 016639 NM 003790 NM 012452 NM 052945 NM 003820 NM 002507 NM 001192 NM 004195 NM 152222 NM 018647 NM 022336 NM 014452 NM 021783 Unknown

NM 011609 NM 011610 NM 010736 NM 011659 NM 011611 NM 007987 Unknown L24495 NM 009401 NM 011612 Unknown NM 020275 NM 024290 NM 023680 NM 009399 NM 008764 NM 013749 NM 033042 NM 021349 NM 028075 Unknown NM 033217 NM 011608 NM 009400 Unknown NM 013869 NM 010100 NM 052975 Unknown NM 175649

TNFRSF1A TNFRSF1B TNFRSF3 TNFRSF4 TNFRSF5 TNFRSF6 TNFRSF6B TNFRSF7 TNFRSF8 TNFRSF9 TNFRSF10A TNFRSF10B TNFRSF10C TNFRSF10D TNFRSF11A TNFRSF11B TNFRSF12A TNFRSF12 TNFRSF13B TNFRSF13C TNFRSF14 TNFRSF16 TNFRSF17 TNFRSF18 TNFRSF19L TNFRSF19

Hs.159 Hs.256278 Hs.1116 Hs.129780 Hs.25648 Hs.82359 Hs.348183 Hs.355307 Hs.1314 Hs.73895 Hs.249190 Hs.51233 Hs.119684 Hs.129844 Hs.114676 Hs.81791 Hs.355899 Hs.26401 Hs.158341 Mm.131257 Hs.279899 Hs.1827 Hs.2556 Hs.212680 Hs.79707 Hs.283615 Hs.58346 Hs.159651 Hs.302017 Unknown

Mm.1258 Mm.2666 Mm.3122 Mm.13885 Mm.4966 Mm.1626 Unknown Mm.121 Mm.12810 Mm.198677 Unknown Mm.193430 Mm.157724 Mm.156947 Mm.6251 Mm.15383 Mm.28518 Mm.101198 Mm.143787 Mm.131257 Unknown Mm.103727 Mm.12935 Mm.3180 Unknown Mm.21526 Mm.89944 Mm.200792 Unknown Unknown

TNFRSF21 TNFRSF24-pending

184

Introduction / Cytokine & Growth Factor Reviews 14 (2003) 181–184

the signal transduction paradigms established for TNFR superfamily. The adaptability of the TNF superfamily is evident at several levels including organ development, tissue homeostasis and structure. Mikkola and Thesleff (chapter 3) discuss ectodermal organ development mediated by EDA1–EDAR system and Rabizadeh and Bredesen (chapter 4) review the NGF receptor systems and its functions related to death and survival signaling. Wiley and Winkles (chapter 5) look at the emerging role of TWEAK–Fn14 system in angiogenesis, and the TRANCE system as a critical factor in bone morphogenesis and lymphoid organogenesis is reviewed by Walsh and Choi (chapter 6). The size of the TNF superfamily appears to have grown in a large part by gene duplication as many of the TNF and TNFR genes are linked in discrete loci reflecting their evolutionary derivation and conserved functions. The TNF superfamily is found only in vertebrates, although many of the signaling proteins are found in more primitive organisms clearly indicating that their advent is relatively recent. Given the predominance the TNF superfamily has in regulating immunity the expansion of the TNF superfamily likely arose coincident with the evolution of adaptive immunity. For example, the most obvious are those TNF receptors found on chromosome (Ch) 12p13 (TNFR1, LT␤R and CD27), which underwent duplication and translocation events giving rise to the larger locus of TNFR on Ch 1p36 (TNFR2, HVEM, OX40, CD30, AITR, 4-1BB and DR3) (Fig. 1A). These receptors engage ligands closely related to TNF that map to the major histocompatibility complex (MHC) on human Ch6 (TNF, LT␤ and LT␣) and the MHC paralogous regions on Ch1, 9 and 19. These ligands are highly related as reflected in their conserved chromosomal location, transcriptional orientation, amino acid homology and by their extensive shared receptor usage. The common theme that emerges for the TNF ligands in the MHC paralogous regions is regulating the life style of T cells. The role of the costimulatory systems, OX40 and 4-1BB in the immunobiology of T cells is evaluated by Croft (chapter 7). Nedospasov and coworkers (chap-

ter 8) discuss lymphotoxin’s role in lymphoid organogenesis, and Granger and Rickert (chapter 9) elaborate on the emerging role of LIGHT in adaptive immunity and pathogenesis. By contrast, the TNF-related cytokines that modulate B cells lie outside the MHC paralogous regions. In two articles on regulation of B lymphocytes, Bishop and Hostager (chapter 10) focus on the CD40 system and Mackay and Ambrose (chapter 11) discuss the BAFF system including APRIL and TWEAK, which rival the TNF–LT␣␤ system in complexity (Fig. 1B). Homeostasis of the immune system is controlled in part by a balance between cell survival and death. Underlying the complex position the TNF family has evolved in regulating immunity are the critical roles played by death receptors. Lee and Ferguson (chapter 12) argue that the territory of the Fas system is not only involved in the homeostasis of the immune system, but expands to angiogenesis and tumor progression. The TRAIL receptor system of death consists of four distinct receptors for a single ligand, whose function is likely to be as an interferon-regulated antiviral system used by NK, DC and CTL, yet ultimately may be utilized as an anti-tumor therapy as pointed out by Almasan and Ashkenazi (chapter 13). The cell survival and death pathways activated by the TNF superfamily provide a powerful selection pressures on viral pathogens. In this context, Benedict (chapter 14) examines the molecular details of viral manipulation of the TNF signaling pathway. 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 ideas and approaches that may reveal fundamental principles common to the entire family. Carl F. Ware Division of Molecular Immunology La Jolla Institute for Allergy and Immunology 10355 Science Center Drive, San Diego, CA 92121, USA Tel.: +1-858-678-4660; fax: +1-858-558-3595 E-mail address: [email protected] (C.F. Ware) URL: http://www.liai.org