First printed in R&D Systems' 1997 Catalog.
For almost a decade, considerable effort has been exerted to identify T cell-derived molecules that are unique to the activation state of a T cell or specific to T cell functions.1-4 The recent discovery of such molecules, coupled with their sequence comparisons to known gene families and superfamilies, has contributed to an overall understanding of the processes involved in, and the consequences of, T cell activation. One such recently discovered molecule is CTLA-8, a novel 20 kDa secreted glycoprotein that appears to be part of a unique ligand-receptor system that regulates the production of various cytokines.5, 6 Although originally named as a member of the CTLA (cytotoxic T cell lymphocyte-associated antigen) series, this factor has little or nothing in common with the other members of this family of factors and, in fact, the name seems to have resulted from a mistaken assumption. CTLA-1, 3, 5, 6 and 7 are all serine proteases,1, 2, 7, 8 while CTLA-2 (alpha and beta forms) is a cysteine protease,9 and CTLA-4 is one of two transmembrane receptors for the B7 (CD80 and CD86) family of counter-receptors.7, 10, 11 Because CTLA-8 is a secreted factor and because its biological activities classify it as a cytokine, the designation IL-17 has more recently been suggested for this factor.
|Figure 1. Proposed pathway for IL-17 in hematopoiesis.|
Interleukin 17 (IL-17) was originally cloned from a T cell hybridoma produced by fusion of a mouse cytotoxic T cell clone and a rat T cell lymphoma.3 This report assumed that the factor isolated from these cells was derived from the mouse CTLs and named this protein CTLA-8. However, more recent studies now suggest that what was thought to be a mouse sequence was actually derived from the rat lymphoma and the designation as a CTLA factor was a misnomer.12, 13 The human equivalent of CTLA-8 was cloned based on its homology to the rodent sequence and to an open reading frame of Herpesvirus saimiri and was designated IL-17.5, 14 In addition to the rat and human factors, mouse IL-17 has also been cloned.12, 13
Human IL-17 is a variably glycosylated, 20-30 kDa homodimeric polypeptide reportedly secreted by CD4+ activated memory (CD45+RO+) T cells.5, 14 The human IL-17 gene codes for a 155 amino acid (aa) residue protein that consists of a 19 aa residue signal sequence and a 136 aa residue mature segment. Within the mature polypeptide, there are six cysteine residues and one potential N-linked glycosylation site.5, 14 Dimerization is achieved through intermolecular cysteine bonds.5 Rat IL-17 is a 150 aa residue polypeptide with a signal sequence of 13 aa residues, and a mature polypeptide length of 137 aa residues.5, 14 Mouse IL-17 is a 158 aa residue polypeptide with a predicted signal sequence of 21 aa residues and a mature polypeptide length of 137 aa residues.13 Mouse and rat IL-17 show 87.3% sequence identity to each other at the amino acid level.13 Human IL-17 shows amino acid sequence identity of 62.5% and 58% to the mouse and rat sequences, respectively.13
The amino acid residue sequence for IL-17 shares remarkable homology to that of the thirteenth open reading frame (ORF-13) of Herpesvirus saimiri (HVS), a gamma-herpesvirus responsible for a devastating lymphoproliferative disease in New World primates.3, 12, 14 Over the 151 aa residues that make up the HVS ORF-13 gene, there is 57% aa residue identity to rat IL-17,3, 13 and 72% aa residue identity to human IL-17.5, 13 The greater homology between the human and virus sequences has prompted the suggestion that the virus, at some time in the distant past, "hijacked" a portion of the human IL-17 gene, thus providing a survival advantage to the virus during natural infection.11, 12 Such a "commandeering" of mammalian cytokine genes by viruses is not uncommon. Other "incorporations" include the encoding of a soluble type I TNF receptor by rabbit Shope fibroma virus,15 the existence of a soluble type II IL-1 receptor in vaccinia virus,16, 17 the presence of an IL-10 homologue in the human Epstein-Barr virus,18, 19 and a potential for synthesis of a chemokine receptor by the same HSV.20 The advantage that a viral cytokine ligand or receptor gene might provide in promoting its own survival may transcend a simple "virus-persists/virus-eliminated" outcome. For example, when the soluble IL-1 type II receptor of the vaccinia virus, which binds and neutralizes only IL-1 beta, is deleted experimentally, the clinical symptoms of animals infected with this mutant form of vaccinia become much more severe relative to animals whose virus possesses the soluble receptor.16 This suggests that, in some cases, overall viral success is best guaranteed by limiting secondary, inflammation-induced tissue damage in the host.16
A receptor for IL-17 has been isolated from mouse EL4 thymoma cells.12 Approximately 120 kDa in size, this (mature) receptor is a type I transmembrane glycoprotein 833 aa residues in length, with a 291 aa residue extracellular segment, a 21 aa residue transmembrane domain, and a 521 aa residue cytoplasmic region.12 The extracellular segment contains eight potential N-linked glycosylation sites plus twelve cysteines, none of which form immunoglobulin-like domains. In addition, there is no suggestion that this receptor belongs to the NGF R/TNF R family, and the extracellular region lacks the ternary structure-maintaining WSXWS motif characteristic of hematopoietin receptors.21 This general lack of receptor family identity also carries over into the cytoplasmic region as there is no identifiable tyrosine kinase homology region(s). There are, however, acidic and serine-rich regions that are similar to regions found in the IL-2 R beta chain, the IL-4 R and the G-CSF R. These, coupled with an eleven aa residue membrane-proximal motif that is highly conserved among cytokine receptors, suggests that this novel receptor likely shares some characteristics with other well known class I cytokine receptors.21, 22 Cell lines known to express IL-17R include EL4 T cell thymoma cells, D11 fetal hepatocytes, 3T3 fibroblasts, H7 mast cells, 70Z/3 pre-B cells, BB4 muscle cells and 1EC6 intestinal epithelial cells.12 Finally, the mouse IL-17 R has also been found to bind rat and human IL-17.5, 12, 13
Although limited in number, studies now suggest that IL-17 may be a major vehicle by which T cells communicate with the hematopoietic system. In particular, fibroblasts, when cultured in the presence of IL-17, are able to sustain CD34+ hematopoietic progenitor cells and direct their maturation towards neutrophils.14 The exact pathway(s) involving IL-17 is not clear. However, IL-17 has been demonstrated to induce IL-6, IL-8 and G-CSF production by fibroblasts (and endothelium), and these three cytokines are known to impact hematopoiesis.6, 14 IL-6, for instance, induces hematopoietic progenitor cells to form granulocyte/macrophage colonies,23 while G-CSF, both in vitro24 and in vivo,25 accelerates the formation of neutrophils. IL-8, in contrast, seems to downmodulate the effects of myelopoietic-promoting cytokines, suggesting that IL-17 may ultimately be found to have the ability to fine-tune or impact all general phases of a hematopoietic response.6, 26 Thus, it appears that IL-17 can now be considered the newest T-cell-derived hematopoietic cytokine, joining IL-3,27, 28 IL-4,29 IL-530 and GM-CSF31, 32 as either regulators or co-regulators of hematopoiesis.14
It is not yet clear how widespread the expression of IL-17 is. Early reports implicated T-lymphocytes as the major source of IL-17,5, 6, 14 particularly activated memory CD4+ T cells.14 More recent studies have suggested a different and more restricted expression pattern in mice.13 Expression of mouse IL-17 by various activated T cells could only be detected using PCR analysis. Using Northern analysis only a subset of T cells, alpha beta TCR+CD4-CD8- T cells, were found to express IL-17 at physiologically significant levels.13 These cells are among the first to be activated during immune responses and are capable of producing large amounts of cytokines characteristic of Th2 type responses (IL-4, IL-5, IL-10, and IL-13) as well as factors usually associated with CD8+ T cells (IFN-gamma, TNF-beta, RANTES, granzyme B, and Fas ligand).13 Although these results suggest that IL-17 is not expressed by a wide variety of of cell types, it is possible that other cells may express higher levels of IL-17 when appropriate activation conditions are found. This work also suggests that IL-17 may play a role in the early stages of immune responses.