Regulated expression and function of CD122 (interleukin-2/interleukin-15R-β) during lymphoid development

To determine whether signaling via CD122 (interleukin-2 [IL-2]/IL-15 receptor β-chain) plays a role in regulating the expansion and differentiation of lymphocyte precursors, we have characterized its expression and evaluated its ability to influence the activity of developing lymphoid cells. A significant fraction of Sca1^+Lin^- hematopoietic stem cells in day 12 fetal liver were found to be CD122^+. CD122-mRNA^+ and IL-2-mRNA^+ cells were also localized in embryo sections within pharyngeal blood vessels adjacent to and surrounding the thymic analgen. This distribution is consistent with the migration of CD122^+ progenitor cells from the liver to the developing thymus where a majority of Sca1^+ intrathymic T-cell progenitors were CD122^+. Analysis of CD122 expression in the day 12 fetal liver revealed that the majority of B220^+ cells were CD122^+. Furthermore, CD122 expression was restricted to the earliest B220^+ cells (CD43^+CD24^-; prepro B cells; fraction A) that proliferate vigorously to IL-2 in the absence of any stromal cells, but not to IL-15. Consistent with a role for the IL-2/IL- 2R pathway in lymphocyte development is the progressive loss of B cells seen in IL-2-deficient mice. Together, these observations suggest that CD122 plays a role in regulating normal lymphocyte development in vivo

Thymic Stromal-Cell Abnormalities and Dysregulated T-Cell Development in IL-2-Deficient Mice

The role that interleukin-2 (IL-2) plays in T-cell development is not known. To address this issue, we have investigated the nature of the abnormal thymic development and autoimmune disorders that occurs in IL-2-deficient (IL-2(–/–)) mice. After 4 to 5 weeks of birth, IL-2(–/–) mice progressively develop a thymic disorder resulting in the disruption of thymocyte maturation. This disorder is characterized by a dramatic reduction in cellularity, the selective loss of immature CD4(-)8(-) (double negative; DN) and CD4(+)8(+) (double positive; DP) thymocytes and defects in the thymic stromal-cell compartment. Immunohistochemical staining of sections of thymuses from specific pathogen-free and germ-free IL-2(–/–) mice of various ages showed a progressive ,loss of cortical epithelial cells, MHC class II-expressing cells, monocytes, and macrophages. Reduced numbers of macrophages were apparent as early as week after birth. Since IL-2(–/–) thymocyte progenitor populations could mature normally on transfer into a normal thymus, the thymic defect in IL-2(–/–) mice appears to be due to abnormalities among thymic stromal cells. These results underscore the role of IL-2 in maintaining functional microenvironments that are necessary to support thymocyte growth, development, and selection

Calmodulin-dependent Protein Kinase IV Regulates Hematopoietic Stem Cell Maintenance

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Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy

The role of interleukin-2 in hematopoiesis

The cells that make up the blood and the immune system all derive from a common progenitor, the hematopoietic stem cell. The generation of mature hematopoietic cells from this progenitor involves commitment to particular lineages and induction of genetic programs appropriate to each mature cell type, processes that are intricately regulated by the hematopoietic microenvironment. Our studies have focused on the regulation of hematopoiesis by soluble growth factors. Based on the fact that interleukin 2 (IL2) is able to influence the activity of most mature hematopoietic cells, we hypothesized that it can regulate immature hematopoietic cell development as well. To test this hypothesis, we investigated the expression of IL2 receptors on developing hematopoietic cell populations, and found that the IL2 receptor $\beta$ chain (CD122) is expressed by multiple hematopoietic cell progenitors in the fetal liver and bone marrow. Moreover, we showed that at the time these CD122\sp{+} progenitor populations are present, IL2 is produced by immature granulocytes in situ, suggesting that IL2 is available to interact with receptor-bearing cells and influence their development. To determine whether IL2 is required for hematopoiesis, we examined hematopoietic cells from IL2-deficient mice. In this system, we showed that in the absence of IL2, mice exhibit a severe hematopoietic disorder that includes a loss of developing B cells in the bone marrow and developing T cells in the thymus. In addition, these mice show a loss of mature granulocytes and erythrocytes in the bone marrow, with a concomitant increase in immature cells of these lineages. Our examination of the mechanistic basis of these disorders revealed both inherent defects in hematopoietic progenitor cell development and abnormalities in the hematopoietic microenvironment, such as overproduction of the inhibitory cytokines tumor necrosis factor $\alpha$ and interleukin 4 by myeloid cells, and a dramatic loss of developing and mature stromal cells. Together, the studies presented in this dissertation demonstrate a critical requirement for IL2 in hematopoiesis

The role of interleukin-2 in hematopoiesis

The cells that make up the blood and the immune system all derive from a common progenitor, the hematopoietic stem cell. The generation of mature hematopoietic cells from this progenitor involves commitment to particular lineages and induction of genetic programs appropriate to each mature cell type, processes that are intricately regulated by the hematopoietic microenvironment. Our studies have focused on the regulation of hematopoiesis by soluble growth factors. Based on the fact that interleukin 2 (IL2) is able to influence the activity of most mature hematopoietic cells, we hypothesized that it can regulate immature hematopoietic cell development as well. To test this hypothesis, we investigated the expression of IL2 receptors on developing hematopoietic cell populations, and found that the IL2 receptor $\beta$ chain (CD122) is expressed by multiple hematopoietic cell progenitors in the fetal liver and bone marrow. Moreover, we showed that at the time these CD122\sp{+} progenitor populations are present, IL2 is produced by immature granulocytes in situ, suggesting that IL2 is available to interact with receptor-bearing cells and influence their development. To determine whether IL2 is required for hematopoiesis, we examined hematopoietic cells from IL2-deficient mice. In this system, we showed that in the absence of IL2, mice exhibit a severe hematopoietic disorder that includes a loss of developing B cells in the bone marrow and developing T cells in the thymus. In addition, these mice show a loss of mature granulocytes and erythrocytes in the bone marrow, with a concomitant increase in immature cells of these lineages. Our examination of the mechanistic basis of these disorders revealed both inherent defects in hematopoietic progenitor cell development and abnormalities in the hematopoietic microenvironment, such as overproduction of the inhibitory cytokines tumor necrosis factor $\alpha$ and interleukin 4 by myeloid cells, and a dramatic loss of developing and mature stromal cells. Together, the studies presented in this dissertation demonstrate a critical requirement for IL2 in hematopoiesis

Stem cells in cancer initiation and progression.

While standard therapies can lead to an initial remission of aggressive cancers, they are often only a transient solution. The resistance and relapse that follows is driven by tumor heterogeneity and therapy-resistant populations that can reinitiate growth and promote disease progression. There is thus a significant need to understand the cell types and signaling pathways that not only contribute to cancer initiation, but also those that confer resistance and drive recurrence. Here, we discuss work showing that stem cells and progenitors may preferentially serve as a cell of origin for cancers, and that cancer stem cells can be key in driving the continued growth and  functional heterogeneity of established cancers. We also describe emerging evidence for the role of developmental signals in cancer initiation, propagation, and therapy resistance and discuss how targeting these pathways may be of therapeutic value