Absence of an Essential Role for Thymic Stromal Lymphopoietin Receptor in Murine B-Cell Development

Abstract

The murine cytokine thymic stromal lymphopoietin (TSLP) supports the development of B220⁺ IgM⁺ immature B cells and induces thymocyte proliferation in vitro. Human TSLP, by contrast, activates CD11c⁺ dendritic cells, but not B or T cells. Recent studies have demonstrated that the receptor for TSLP consists of a heterodimer of the interleukin 7 (IL-7) α chain and a novel protein that resembles the hematopoietic cytokine receptor common γ chain. We examined signal transduction by the γ-like chains using chimeric receptor proteins. The cytoplasmic domain of the human, but not of the murine, γ-like chain, activates Jak2 and Stat5 and supports the proliferation of hematopoietic cell lines. In order to assess the role of the murine γ-like chain in vivo, we generated γ-like chain-deficient mice. Receptor-deficient mice are unresponsive to TSLP but exhibit no obvious phenotypic defects. In particular, hematopoietic cell development appeared normal. B-cell development, including the IgM⁺ compartment, was unaffected by loss of the TSLP pathway, as were T lymphopoiesis and lymphocyte proliferation in vitro. Cytokine receptors that utilize the common γ chain signal through the lymphocyte-specific kinase Jak3. Mice deficient in Jak3 exhibit a SCID phenotype but harbor a residual B220⁺ splenic lymphocyte population. We demonstrate here that this residual lymphocyte population is lost in mice lacking both the γ-like chain and Jak3.