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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...

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The unique combination of adhesion molecules expressed on endothelial cells is thought to mediate the specificity of leukocyte-endothelial cell interactions. In this study, murine endothelial cell lines were used as a model to identify novel adhesion molecules that participate in these cellular interactions. Lymphocyte adhesion to the continuous endothelial cell lines mHEVa and mHEVc required alpha 4-integrin. Interestingly, lymphocyte alpha 4-integrin bound to VCAM-1 as well as an unknown ligand on the mHEVa cell line. We have demonstrated that this VCAM-1-independent adhesion to the mHEVa cells was not mediated by other known alpha 4-integrin ligands (fibronectin, alpha 4-integrin itself, or MAdCAM-1). Two novel alpha 4-integrin ligands (p50 and p10) were isolated from the mHEVa cell line but not the mHEVc cell line by B cell alpha 4-integrin-specific ligand binding of radiolabeled mHEV cell membrane proteins. These results provide the first direct evidence that novel ligands for alpha 4-integrin exist on membranes from endothelial cells.