Human Thymic Stromal Lymphopoietin Preferentially Stimulates Myeloid Cells

Abstract

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.

Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP

“…Stained cells were analyzed on a FACScan flow cytometer (Becton Dickinson). 17 . Results are expressed as mRNA levels relative to ubiquitin.…”

“…Mouse TSLP supports murine early B and T cell developments 18,19 and does not appear to have any biological effects on murine DCs (unpublished data). In contrast, human TSLP activates CD11c + DCs, but does not appear to have any direct biological effects on B cells, T cells, NK cells, neutrophils or mast cells 17 . This is in accordance with the coexpression of IL-7Rα chain and TSLPR mRNA in CD11c + DCs, but not in other cell types.…”

“…Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, cloned from a murine thymic stromal cell line 13 . The TLSP receptor is a heterodimer that consists of the IL-7 receptor α chain (IL-7Rα) and a common γ-like receptor chain called TSLP receptor (TSLPR) [14][15][16][17] . Mouse TSLP supports murine early B and T cell developments 18,19 and does not appear to have any biological effects on murine DCs (unpublished data).…”

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

“…As noted above, whereas mouse CD4 ϩ T cells respond directly to TSLP (10), human TLSP has been reported to only activate peripheral blood CD11c ϩ DCs but to not act directly on other DCs or T or B cells (15,16). We analyzed TSLPR expression on resting and activated human CD4 ϩ T cells and the responsiveness of these cells to TSLP to determine whether TSLP indeed exhibited as dramatic a species variation between humans and mice as is seen with IL-7, with mice but not humans requiring IL-7 for B cell development (6 -9).…”

“…TSLPR KO mice have a defective lung inflammatory allergic response, but this is reversed by adoptive transfer of WT CD4 ϩ T cells (11). In humans, TSLP was shown to regulate Th2 allergic responses by acting directly on dendritic cells (DCs), but not on CD4 ϩ T cells, with TSLPactivated DCs in turn stimulating CD4 ϩ T cells (15,16). Because of the surprising apparent difference that mouse but not human TSLP could directly act on CD4 ϩ T cells, we decided to investigate if human CD4 ϩ T cells expressed TSLP receptors and the responsiveness of these cells to TSLP.…”