Overexpression of murine TSLP impairs lymphopoiesis and myelopoiesis

Abstract

The role of thymic stromal cell-derived lymphopoietin (TSLP) in regulating hematopoiesis is poorly characterized, so we investigated its regulatory effects in vivo using TSLP transgenic mice. Overexpression of TSLP disrupted hematopoietic homeostasis by causing imbalances in lymphopoiesis and myelopoiesis. Mice harboring a TSLP transgene had 5-to 700-fold fewer B and T precursors and no detectable pre-B lymphocyte colonyforming activity in the marrow or spleen. Conversely, TSLP transgenic mice possessed 15 to 20 times more splenic myeloid precursors than their littermates, and progenitor activity of the granulocyteerythrocyte-macrophage-megakaryocyte colony-forming units was significantly el- IntroductionGrowth and differentiation of leukocyte progenitors are critical for the establishment and normal function of the mammalian immune system. Appropriate development within the myeloid lineage contributes significantly to protective innate immunity, and the maturation of cells from the lymphoid lineage is essential for adaptive immune responses to foreign antigens. Several studies have shown that failure to maintain homeostasis between myeloid and lymphoid development can cause profound pathophysiologic consequences. [1][2][3][4] Multiple cytokines regulate the homeostatic mechanisms responsible for maintaining a physiologic balance between leukocytes in the lymphoid and myeloid lineages. 5 The cytokine thymic stromal cell-derived lymphopoietin (TSLP) was originally identified as a biologic activity present in conditioned medium from a thymic medullary stromal cell line. 6 This cytokine promoted both proliferation and differentiation of B220 ϩ pro-B cells from committed B220 Ϫ fetal liver progenitors. In long-term bone marrow cultures, TSLP acted at a later stage of B-lineage development leading to an increase in the number of immature B lymphocytes. 7 These studies suggested that TSLP had overlapping functions with a related cytokine, interleukin 7 (IL-7). In fact, TSLP and IL-7 are all members of a hematopoietic cytokine family that includes IL-2, IL-4, IL-9, IL-13, In addition, the receptors for these cytokines share common receptor components.TSLP exerts its biologic effects through its receptor, which is an IL-7R␣ chain and TSLPR heterodimer. Engagement of the TSLPR by its ligand initiates biochemical signals triggering the activation of STAT5 and src-family tyrosine kinases. 7,[11][12][13] Recently, Isaksen et al 12 demonstrated that a single tyrosine residue in the cytoplasmic domain of TSLPR is critical for TSLP-mediated proliferation. Src-family kinases, as well, are important for cell proliferation induced by TSLP. 12 Several src kinases are known oncogenes [14][15][16][17] ; and given that they play an indispensable role in proliferation mediated by TSLP, aberrant expression of this cytokine could result in uncontrolled growth of TSLP-responsive cells and loss of hematopoietic homeostasis. Consequently, it is important to have a clear understanding of the role of TSLP in lymphohematopoiesis. Yet in thi...

Intradermal Administration of Thymic Stromal Lymphopoietin Induces a T Cell- and Eosinophil-Dependent Systemic Th2 Inflammatory Response

“…1G). Additional analysis of serum Igs from TSLP-injected mice showed an increase in serum IgG1 concentration and no change in IgG2a concentration (data not shown), consistent with a Th2 response and previous observations in TSLP transgenic mice (10,12,13). …”

“…These data, taken together with the data from the IL-4-and IL-13-deficient mice, strongly suggest a role for IL-5 and eosinophils in the pathology arising from TSLP administration. In agreement with this, increased circulating levels of IL-5 have been reported in transgenic mice systemically overexpressing TSLP (10). Injection of TSLP into eosinophil-deficient mice resulted in a striking loss of inflammatory infiltrate along with the loss of prototypical Th2 responses.…”

“…In transgenic mouse models, overexpression of TSLP leads to systemic inflammation (9,10), and when specifically expressed in airway epithelial cells or keratinocytes leads to the development of asthma and AD-like phenotypes, respectively (11)(12)(13). Similarly, in nontransgenic models, aberrant TSLP expression can be induced by keratinocyte-specific ablation of retinoid X receptors or topical application of vitamin D3 and lowcalcemic analogues.…”

Gene Expression Profiles of Peripheral and Cord Blood Mononuclear Cells Altered by Thymic Stromal Lymphopoietin

“…Thus, IDO works as an immune suppressor, generally. In contrast, TSLP transgenic mice developed to systemic inflammation including glomerulonephritis (28,29).…”

A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis

“…Francis et al 420 haematologica | 2016; 101(4) +T stroma showed serum hTSLP levels that were low but detectable (4-10 pg/mL) (data not shown). To achieve higher levels of sustained hTSLP expression, NSG mice were injected with 3 doses of 1x10 7 +T or -T stroma over a 1-week period (loading dose) followed by weekly injections of 1x10 7 stromal cells. Serum collected at weekly time points showed serum hTSLP levels of approximately 80 pg/mL following the initial 3 doses of +T stroma but quickly dropped to 15-20 pg/mL with +T stroma injections ( Figure 2C, left panel).…”