SummaryAnalysis of the cDNA encoding murine interleukin (IL) 17 (cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame ofHerpesvirus saimiri. Here we report on the cloning of human , the human counterpart ofmurine IL-17. hlL-17 is a glycoprotein of 155 amino acids secreted as an homodimer by activated memory CD4 + T cells. Although devoid of direct effects on cells of hematopoietic origin, hlL-17 and the product of its viral counterpart, Olq.F13, stimulate epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte--colony-stimulating factor, as well as prostaglandin E2. Furthermore, when cultured in the presence of hlL-17, fibroblasts could sustain the proliferation of CD34 + hematopoietic progenitors and their preferential maturation into neutrophils. These observations suggest that hlL-17 may constitute (a) an early initiator of the T cell-dependent inflammatory reaction; and (b) an element of the cytokine network that bridges the immune system to hematopoiesis.T lymphocytes produce an array of small proteins that are involved in cell growth, inflammation, immunity, differentiation, and repair. These protein mediators referred to as cytokines are not produced constitutively by T cells, but rather are induced after receptor-mediated T cell activation (1, 2). Murine cytotoxic T lymphocyte associated antigen-8 (mCTLA8) 1, a cDNA previously cloned by lq.ouvier et al. (3) from a T cell subtraction library, displays some of the features ofa cytokine gene: in particular, a pre1Abbreviations used in this paper: hlL-17, human IL-17; HVS, Herpesvirus saimiri; ORF13, open reading frame 13; mCTLA8, murine cytotoxic T lymphocyte-associated antigen 8; PGE 2, prostaglandin E2; PI, PMA and ionomycin.Parts of this work were presented at

Interleukin (IL)-13 elicits a subset of the biological activities of the related IL-4. The basis of this functional similarity is that their specific cell-surface receptors (called IL-13R and IL-4R) are distinct, yet are complex and share a common subunit(s). The IL-4R primary binding subunit (called IL-4R alpha) does not by itself bind IL-13. We show that the ability of IL-13 to partially compete for IL-4 binding to some human cell types depended on co-expression of IL-4R and IL-13R. However, IL-13 binding was always associated with IL-4 binding. Hyper-expression of IL-4R alpha on cells expressing both IL-4R and IL-13R decreased their binding affinity for IL-4, abrogated the ability of IL-13 to compete for IL-4 binding, and yet had no effect on IL-13R properties. Anti-human IL-4R alpha monoclonal antibodies which blocked the biological function and binding of IL-4 also blocked the function and binding of IL-13. These data show that IL-4R alpha is a secondary component of IL-13R.

This paper describes an antibody (mAb 7D6) that specifically recognizes human follicular dendritic cells (FDCs). By expression cloning, a cDNA clone encoding for the long human CR2/ CD21 isoform (CD21L) that contains an additional exon (10a) was isolated. We demonstrated that FDCs selectively express CD21L, while B cells selectively express the short CR2/CD21 lacking exon 10a (CD21S). By screening mouse Ltk− cells transfected with the CD21L cDNA, we further showed that the other two anti–human FDC mAbs DRC-1 and KiM4 also recognize CD21L. Thus, CD21L represents the first characterized human FDC-specific molecule, which may confer unique functions of FDCs in germinal center development.

We have produced and characterized a new CD40 monoclonal antibody, mAb 89, which in the presence of anti-IgM antibodies co-stimulates to induce B cell proliferation. mAb 89 activates resting B cells as shown by an increase in cell volume and an enhanced subsequent proliferation of B cells in response to anti-IgM antibody. However, mAb 89 does not prepare B cells to respond to the growth-promoting activity of interleukin (IL) 2 or IL 4. Unlike IL 2 and IL 4, mAb 89 only weakly stimulates the proliferation of anti-IgM pre-activated B cells. Thus, the activating properties of anti-CD40 are likely to explain its co-stimulatory effect on B cells. Interestingly, the anti-CD40 mAb 89 was found to act in synergy with IL 4, but not with IL 2, in co-stimulation and restimulation assays. In this respect, anti-CD40 does not induce a significant increase of B cell surface IL 4 receptors while IL 4, but not IL 2, induces a twofold increase of the CD40 antigen expression. Thus the synergistic interaction between IL 4 and anti-CD40 may be related to the IL 4-dependent increase of CD40 antigen expression.

Using the mouse interleukin 4 (IL-4) receptor cDNA as a probe, we isolated a cDNA encoding the human IL-4 receptor (hIL-4 receptor) from a multifactor-responsive human myeloid cell line, TF1. The cDNA encodes for an open reading frame of 825 amino acids including a signal sequence (25 amino acids), the external domain (207 amino acids), a transmembrane domain (24 amino acids), and a large cytoplasmic domain (569 amino acids). The human IL-4 receptor has a 65% identity with the mouse IL-4 receptor at the nucleic acid level and retains the typical structural motif of the previously described cytokine receptor family. COS7 cells transfected with the full-length cDNA expressed high levels (140,000 sites/cell) of IL-4 binding sites, with a Kd = 80 pM, an affinity identical to that of the original TF1 cells. Similar to IL-4 responsive cells, cross-linking of [125I]IL-4 to COS7 cells transfected with the cDNA showed a major protein of 130-150 kd and minor species of 55-85 kd.

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Human interleukin 4 (IL4) acts on various hematopoietic cell types through interaction with a specific cell surface receptor (IL4R), whose cDNA has been cloned. We have produced a cDNA encoding a soluble form of the extracellular domain of the human IL 4R (sIL4R) and describe here the capacity of sIL4R to antagonize the in vitro activities of IL4 on normal B and T lymphocytes. sIL4R inhibited IL4-induced proliferation of both phytohemagglutinin-preactivated peripheral blood mononuclear cells (PBMC) and anti-IgM co-stimulated tonsil B cells with similar efficiency. This inhibitory activity was specific since sIL4R did not affect IL2-dependent proliferation of these cells. sIL4R also blocked IL4-dependent induction of the low-affinity receptor for IgE on B cells and inhibited IgE production by IL4-activated PBMC. Thus, in contrast to the IL6R extracellular domain which stimulates IL6 biological activity, the IL4R extracellular domain is a powerful antagonist of its specific ligand.

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