IL-23 is a heterodimeric cytokine composed of the IL-12p40 “soluble receptor” subunit and a novel cytokine-like subunit related to IL-12p35, termed p19. Human and mouse IL-23 exhibit some activities similar to IL-12, but differ in their capacities to stimulate particular populations of memory T cells. Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rβ1. However, it does not use IL-12Rβ2. In this study, we identify a novel member of the hemopoietin receptor family as a subunit of the receptor for IL-23, “IL-23R.” IL-23R pairs with IL-12Rβ1 to confer IL-23 responsiveness on cells expressing both subunits. Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R. Anti-IL-12Rβ1 and anti-IL-23R Abs block IL-23 responses of an NK cell line and Ba/F3 cells expressing the two receptor chains. IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3. The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12Rβ2, respectively. The human IL-23R gene is on human chromosome 1 within 150 kb of IL-12Rβ2.
CD4+ T regulatory type 1 (Tr1) cells suppress Ag-specific immune responses in vitro and in vivo. Although IL-10 is critical for the differentiation of Tr1 cells, the effects of other cytokines on differentiation of naive T cells into Tr1 cells have not been investigated. Here we demonstrate that endogenous or exogenous IL-10 in combination with IFN-α, but not TGF-β, induces naive CD4+ T cells derived from cord blood to differentiate into Tr1 cells: IL-10+IFN-γ+IL-2−/lowIL-4−. Naive CD4+ T cells derived from peripheral blood require both exogenous IL-10 and IFN-α for Tr1 cell differentiation. The proliferative responses of the Tr1-containing lymphocyte populations, following activation with anti-CD3 and anti-CD28 mAbs, were reduced. Similarly, cultures containing Tr1 cells displayed reduced responses to alloantigens via a mechanism that was partially mediated by IL-10 and TGF-β. More importantly, Tr1-containing populations strongly suppressed responses of naive T cells to alloantigens. Collectively, these results show that IFN-α strongly enhances IL-10-induced differentiation of functional Tr1 cells, which represents a first major step in establishing specific culture conditions to generate T regulatory cells for biological and biochemical analysis, and for cellular therapy to induce peripheral tolerance in humans.
The sequence of a novel hemopoietic cytokine was discovered in a computational screen of genomic databases, and its homology to mouse thymic stromal lymphopoietin (TSLP) suggests that it is the human orthologue. Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R α-chain. Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5. Human TSLPR and IL-7Rα are principally coexpressed on monocytes and dendritic cell populations and to a much lesser extent on various lymphoid cells. In accord, we find that human TSLP functions mainly on myeloid cells; it induces the release of T cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c+ dendritic cells, as evidenced by the strong induction of the costimulatory molecules CD40 and CD80 and the enhanced capacity to elicit proliferation of naive T cells.
We have isolated the human cDNA homologue of a mouse helper T-cell-specific cDNA sequence, called P600, from an activated human T-cell cDNA library. The human cDNA encodes a secreted, mainly unglycosylated, protein with a relative molecular mass of -10,000. We show that the human and mouse proteins cause extensive morphological changes to human monocytes with an associated up-regulation of major histocompatibility complex class II antigens and the low-affinity receptor for immunoglobulin E (FcERII or CD23). In addition, they stimulate proliferation of human B cells that have been activated by anti-IgM antibodies or by anti-CD40 monoclonal antibodies presented by a mouse Ltk-cell line transfected with CDw32. Furthermore, the human protein induced considerable levels of IgM and IgG, but no IgA production, in cultures in which highly purified human surface IgD+ or total B cells were cocultured with an activated CD4+ T-cell clone. Based on these findings, we propose that this immunoregulatory protein be designated interleukin 13.
The idiopathic inflammatory myopathies are characterized by antibody- or cell-mediated immune response against unknown muscle tissue antigens. In these diseases a cellular infiltrate, composed of T and B lymphocytes, macrophages and NK cells, may invade muscle tissue with a gradient from the perivascular space to the endomysial compartment. Muscle cells may be actively involved in the processes of mononuclear cell recruitment and activation from the blood stream to the areas of inflammation. In order to verify this hypothesis, cultured human myoblasts were tested for their capacity to express different pro-inflammatory cytokines [IL-1alpha, IL-1beta, IL-6 and tumor necrosis factor (TNF)-alpha] and chemokines (IL-8, MCP-1 and RANTES) at the mRNA level and protein secretion, in the presence of the pro-inflammatory cytokines IFN-gamma and TNF-alpha alone or in combination. We confirmed that human myoblasts expressed IL-1alpha and IL-6 constitutively, while IL-1beta and TNF-alpha are detected only after treatment with pro-inflammatory cytokines; moreover, we observed that TNF-alpha was expressed on an autocrine fashion by myoblasts. IL-8 and RANTES were expressed constitutively while MCP-1 after proper induction. These molecular data were further confirmed by specific ELISA in the supernatant from cultured myoblasts. Our results underline the importance of human myoblasts in the recruitment of leukocytes from the blood stream and, most probably, in the cross-talk between infiltrating inflammatory cells and muscle cells, creating the conditions for a chronic inflammation. Moreover, the capacity of muscle cells to behave as cells of the immune system has to be kept in mind, also in view of i.m. vaccination and use of molecular engineered myoblasts as vehicles in gene therapy.
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