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

Human TLR10 is an orphan member of the TLR family. Genomic studies indicate that TLR10 is in a locus that also contains TLR1 and TLR6, two receptors known to function as coreceptors for TLR2. We have shown that TLR10 was not only able to homodimerize but also heterodimerized with TLRs 1 and 2. In addition, unlike TLR1 and TLR6, TLR10 was expressed in a highly restricted fashion as a highly N-glycosylated protein, which we detected in B cell lines, B cells from peripheral blood, and plasmacytoid dendritic cells from tonsil. We were also able to detect TLR10 in a CD1a+ DC subset derived from CD34+ progenitor cells which resemble Langerhans cells in the epidermis. Although we were unable to identify a specific ligand for TLR10, by using a recombinant CD4TLR10 molecule we also demonstrated that TLR10 directly associates with MyD88, the common Toll IL-1 receptor domain adapter. Additionally, we have characterized regions in the Toll IL-1 receptor domain of TLR10 that are essential in the activation of promoters from certain inflammatory cytokines. Even though TLR10 expression has not been detected in mice, we have identified a partial genomic sequence of the TLR10 gene that was present but nonfunctional and disrupted by a retroviral insertion in all mouse strains tested. However, a complete TLR10 sequence could be detected in the rat genome, indicating that a functional copy may be preserved in this species.

We have isolated a novel cell surface molecule, the human homolog of osteoclast-associated receptor (OSCAR). Unlike mouse OSCAR, hOSCAR is widely transcribed in cells of the myeloid lineage. Notably, hOSCAR is expressed on circulating blood monocytes and CD11c ؉ dendritic cells but not on T and B cells. hOSCAR is continually expressed during differentiation of CD14 ؉ monocytes into dendritic cells and maintained after maturation. hOSCAR associates with the FcR␥ as shown by translocation of FcR␥ to the cell surface in presence of hOSCAR and coimmunoprecipitation from transfected cell lines and ex vivo cells. Engagement of hOSCAR with specific mAb leads to Ca 2؉ mobilization and cytokine release, indicators of cellular activation. Endocytosis of the receptor in dendritic cells was observed, followed by passage of the internalized material into Lamp-1 ؉ and HLA-DR ؉ compartments, suggesting a role in antigen uptake and presentation.Dendritic cells were able to stimulate a T-cell clone specific for an epitope of mouse IgG1 after uptake and processing of the hOSCAR-specific antibody, demonstrating the capacity of this receptor to mediate antigen presentation. hOSCAR thus represents a novel class of molecule expressed by dendritic cells involved in the initiation of the immune response.

The expression of CD40 ligand (CD40L) on activated T cells (CD4+ T cell clone MT9) is diminished when the T cells are cultured in the presence of B cells. This effect, observed both with normal tonsil B cells and with the B cell line JY, was detected after 6 h and sustained at least until 18 h of co-culture. Analysis of mRNA showed that CD40L mRNA levels were not modified after 6 h, but were significantly down-regulated after 18 h of co-culture with B cells. Although CD40L expression could not be detected by a CD40-Fc chimera, the molecule was still expressed at the membrane as shown with a polyclonal antiserum against CD40L (anti-TRAP). In addition, T cells activated in the presence of B cells were stained by a polyclonal antiserum against CD40, without the appearance of CD40 mRNA. These results indicated that a soluble form of CD40 (sCD40) bound to the expressed CD40L on T cells. The existence of sCD40 was confirmed by detection of sCD40 in B cell supernatants using a specific enzyme-linked immunosorbent assay. Collectively, these data show that B cells can regulate the expression of CD40L on activated T cells at least by two different mechanisms.