TSLP or IL‐7 provide an IL‐7Rα signal that is critical for human B lymphopoiesis

Abstract

Thymic stromal lymphopoietin (TSLP) and IL-7 are cytokines that signal via the IL-7 receptor alpha (IL-7Rα) to exert both overlapping and unique functions during early stages of mouse B cell development. In human B lymphopoiesis the requirement for IL-7Rα signaling is controversial and the roles of IL-7 and TSLP are less clear. Here we evaluated human B cell production using novel in vitro and xenograft models of human B cell development that provide selective IL-7 and human TSLP (hTSLP) stimulation. We show that in vitro human B cell production is almost completely blocked in the absence of IL-7Rα stimulation and that either TSLP or IL-7 can provide a signal critical for the production and proliferation of human CD19+ PAX5+ pro-B cells. Analysis of primary human bone marrow (BM) stromal cells show that they express both IL-7 and TSLP providing an in vivo source of these cytokines. Using novel xenograft models we show that the in vivo production of human pro-B cells under the influence of mouse IL-7 is reduced by anti-IL-7 neutralizing antibodies, and this loss can be restored by hTSLP at physiological levels. These data establish the importance of IL-7Rα-mediated signals for normal human B cell production.

Inherited human IFN-γ deficiency underlies mycobacterial disease

“…Our study confirms that MSMD is actually caused by inborn errors of IFN-γ. This experiment of nature rules out the remote but finite possibility that there are other agonists of the IFN-γ receptor, as documented for other receptors such as IL-4Rα, which can be stimulated by IL-4 and IL-13 (82)(83)(84), and IL-7Rα, which can be stimulated by IL-7 and thymic stromal lymphopoietin (TSLP) (85). Mutations of IFNG should thus be considered in patients with MSMD or related infectious diseases, including tuberculosis and other diseases caused by intramacrophagic microorganisms.…”

Expression of Exogenous Cytokine in Patient-derived Xenografts via Injection with a Cytokine-transduced Stromal Cell Line

“…4 The production of control PDX mice that are similarly engineered, are also described. Together control and cytokine-producing PDX create a human TSLP+/− model system that we have successfully used to evaluate the role of TSLP in the in vivo production of normal and malignant human B cells.…”

“…Together control and cytokine-producing PDX create a human TSLP+/− model system that we have successfully used to evaluate the role of TSLP in the in vivo production of normal and malignant human B cells. 4,6 This model is highly relevant to studies of a particular high risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by genetic alterations leading to overexpression of CRLF2. CRLF2 is a receptor for the TSLP cytokine and thus TSLP-induced CRLF2 signaling likely contributes to oncogenesis and progression of CRLF2+ B-ALL.…”

“…2 In this case, mouse IL-7 has sufficient homology with human IL-7 that the mouse cytokine stimulates signaling pathways in human B cell precursors. 2,3,4 However, this is not the case for thymic stromal lymphopoietin (TSLP), 5,6 which among other cytokines (IL-3, granulocyte-macrophage colony stimulating factor (GM-CSF), stem cell factor (SCF), 7 is important for the production of normal and malignant human hematopoietic cells. When mouse and human cytokines show low homology the mouse cytokines do not activate their respective receptors on human cells.…”

“…The stromal-cell mediated cytokine delivery method detailed here was used to develop PDX for evaluating the role of TSLP in normal human B cell development 4,6 and high risk B-cell acute lymphoblastic leukemia. 6 This method provides an alternative cytokine delivery method for use in generating similar models with human cytokines other than TSLP.…”