Common lymphoid progenitors, early B-lineage precursors, and IL-7

Precursors for B lymphocytes develop from semirestricted lymphoid progenitors in the bone marrow. Here we review current knowledge on the cellular stages underlying early B cell development from multipotent progenitor cells, and discuss the factors implicated in the regulation of this process. In particular, we will focus on the role of cytokine receptor signaling in early lymphocyte ontogeny and lymphoid lineage commitment, with an emphasis on the role of interleukin-7 (IL-7) in early lymphocyte development within the bone marrow microenvironment. We will also discuss recent evidence that lymphocytes and subsets of dendritic cells develop from a common pathway, speculating that IL-7 may regulate cell fate decisions in multipotent B/dendritic cell precursors by driving these cells to differentiate into B-lineage-committed cells.     

Common lymphoid progenitors,early B-lineage precursors,and IL-7: characterizing the trophic and instructive signals underlying early B cell development

Precursors for B lymphocytes develop from semirestricted lymphoid progenitors in the bone marrow. Here we review current knowledge on the cellular stages underlying early B cell development from multipotent progenitor cells, and discuss the factors implicated in the regulation of this process. In particular, we will focus on the role of cytokine receptor signaling in early lymphocyte ontogeny and lymphoid lineage commitment, with an emphasis on the role of interleukin- 7 (IL-7) in early lymphocyte development within the bone marrow microenvironment. We will also discuss recent evidence that lymphocytes and subsets of dendritic cells develop from a common pathway, speculating that IL-7 may regulate cell fate decisions in multipotent B/dendritic cell precursors by driving these cells to differentiate into B-lineage-committed cells.     

Interleukin-7 Receptor Signaling Network： An Integrated Systems Perspective

Interleukin-7 （IL-7） is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor （IL-7R）, activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7 receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology. Cellular ＆ Molecular Immunology.     

Overexpression of Bcl-2 does not rescue impaired B lymphopoiesis in IL- 7 receptor-deficient mice but can enhance survival of mature B cells

IL-7 receptor-deficient (IL-7R(-/-)) mice are lymphopenic as a result of defective cell production at early steps in both B and T lymphopoiesis. In the bone marrow, there is an incomplete block in B cell development at the transition from the pro-B to the pre-B cell stage. As a consequence, peripheral lymphoid organs of IL-7R(-/-) mice contain abnormally low numbers of mature surface (s) Ig-expressing B cells and this is accompanied by a relative increase in immature sIg- B cells. Transgenic expression of the anti-apoptotic protein Bcl-2 in IL- 7R(-/-) mice rescues the defect in T cell development and in mature T cell function. The present report shows that constitutive expression of Bcl-2 is incapable of rescuing B lymphopoiesis in IL-7R(-/-) mice but can enhance survival of those mature B cells which escape the developmental arrest. Thus the essential role of IL-7R signaling in B lymphoid cells cannot be replaced by Bcl-2, indicating that in B lymphopoiesis IL-7R signaling is necessary for promoting cell division and/or for inhibiting a Bcl-2-insensitive pathway to apoptosis.      

IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade

IL-21 is a Type I cytokine, which uses the common gamma chain (gamma(c)) in its receptor. As members of the gamma(c) cytokine/cytokine receptors family play crucial role in the differentiation, activation, and survival of lymphocytes, we have investigated if IL-21 could promote T cell survival and thus, contribute to T cell homeostasis and expansion. Unlike most gamma(c) cytokine receptors, we report that IL-21R is constitutively expressed by all mature T lymphocytes and that stromal cells of lymphoid organs are a constitutive source of IL-21. These observations are reminiscent of what is observed for IL-7/IL-7R, which control T cell survival and homeostasis and suggest a role for IL-21 in T cell homeostasis. Indeed, our results show that IL-21 is a survival factor for resting and activated T cells. Moreover, the ability of IL-21 to costimulate T cell proliferation is mediated by enhancing T cell viability. Further investigation of how IL-21R signaling induces T cell survival shows for the first time that IL-21 binding to its receptor activates the PI-3K signaling pathway and induces Bcl-2 expression. Moreover, the activation of the PI-3K signaling pathway is essential for IL-21-mediated T cell survival. Our data provide a new role for IL-21 in the immune system, which might be used to improve T cell homeostasis in immunocompromised patients.     

Role of interleukin-7 in T-cell development from hematopoietic stem cells

Summary: All lymphocytes are derived from hematopoietic stem cells (HSC). The interleukin-7 receptor (IL-7R) transduces non-redundant signals for both T and B-cell development from HSC. The upregulation of the IL-7R occurs at the stage of the clonogenic common lymphoid progenitor, a recently identified population that can give rise to all lymphoid lineages (T, B and natural killer cells) at a single cell level. The IL-7R plays a critical role in the rearrangement of immunoglobulin heavy chain genes required for B-cell development, IL-7R expression is critically regulated in developing thymocytes; thytnocytes that fail the positive selection process down-regulate the IL-7R, but those undergoing positive selection upregulate or maintain IL-7R expression. Recent data indicate that IL-7 signaling enhances the survival of developing thymocytes and mature T ceils, presumably by its upregulating Bcl-2. Detailed analysis of the signaling cascades activated by the IL-7R may help to reveal the differential roles of IL-7 signaling in T and B-cell development.     

Role of B7 signaling in the differentiation of naive CD4+ T cells to effector interleukin-4-producing T helper cells

Signaling through the T cell receptor must be accompanied by costimulatory signals for the differentiation of naive T cells to cytokine-producing effector T helper cells. The costimulatory signal through CD28 is required for T cell activation resulting in increased interleukin (IL)-2 production in vitro, but its role in the production of IL-4 and in the in vivo response is still unclear. We have examined the effects of blocking CTLA-4 (the CD28 homologue) ligand interactions on the in vivo development of IL-4-producing T helper effector cells during a primary mucosal immune response to the nematode parasiteHeligmosomoides polygyrus and during a primary systemic immune response to immunogenic anti-IgD antibodies. Our results demonstrate that CD28 and/or CTLA-4 signaling is required for T cell priming leading to IL-4 cytokine production, B cell activation, and IgE secretion during both immune responses, suggesting that other signaling molecules do not substitute for these molecules in either of these two different immune responses. Furthermore, the CD28 ligands, B7-1 and B7-2, can substitute for each other in providing the required T cell costimulatory ligand interactions during the primary immune response toH. polygyrus. In contrast, memory T cells during the challenge immune response do not require CD28/CTLA-4 ligand interactions for TL-4 production and T helper effector function. *** DIRECT SUPPORT *** A02GS028 00003     

CD40 signaling induces B cell responsiveness to multiple members of the gamma chain-common cytokine family.

CD40 signaling induces B cell proliferative and differentiation responses that can be modulated by many different cytokines. Cytokines in the IL-2 receptor gamma chain (gammac)-common family are known to play an integral role in B cell development. Therefore, we investigated the possibility that CD40 signaling induced B cell responsiveness to multiple gammac-common cytokines and that individual gammac-common cytokines induced distinct B cell responses. B cells were isolated from lymphoid follicles of sheep Peyer's patches (PP) and co-cultured with murine CD40 ligand (mCD40L). CD40 signaling induced PP B cell responsiveness to recombinant human IL-2, IL-4, IL-7 and IL-15. mCD40L-induced B cell growth was enhanced by combining IL-4 with a second gammac-common cytokine and sustained B cell growth required co-stimulation with IL-4 plus IL-2, IL-7 and IL-15. gammac-common cytokine responsiveness remained dependent upon CD40 signaling, and removal of mCD40L resulted in B cell differentiation and cell death. Similar proliferative responses to mCD40L and gammac-common cytokines were observed for both immature (ileal) and mature (jejunal) PP B cells. Finally, the capacity of CD40-activated B cells to respond to multiple gammac-common cytokines was analyzed with individual PP B cell clones. All B cell clones displayed similar proliferative responses to IL-2 but quantitatively different responses to IL-4, IL-7 and IL-15. The biological significance of B cell responsiveness to multiple gammac-common cytokines is discussed.     

SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions

One or more of the signaling lymphocytic activation molecule (SLAM) family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins, i.e., SLAMF1-9, are expressed on most hematopoietic cells. While most SLAMF receptors serve as self-ligands, SLAMF2 and SLAMF4 use each other as counter structures. Six of the receptors carry one or more copies of a unique intracellular tyrosine-based switch motif, which has high affinity for the single SH2-domain signaling molecules SLAM-associated protein and EAT-2. Whereas SLAMF receptors are costimulatory molecules on the surface of CD4+, CD8+, and natural killer (NK) T cells, they also involved in early phases of lineage commitment during hematopoiesis. SLAMF receptors regulate T lymphocyte development and function and modulate lytic activity, cytokine production, and major histocompatibility complex-independent cell inhibition of NK cells. Furthermore, they modulate B cell activation and memory generation, neutrophil, dendritic cell, macrophage and eosinophil function, and platelet aggregation. In this review, we will discuss the role of SLAM receptors and their adapters in T cell function, and we will examine the role of these receptors and their adapters in X-linked lymphoproliferative disease and their contribution to disease susceptibility in systemic lupus erythematosus.     

CD4+ Th2 cells are directly regulated by IL-10 during allergic airway inflammation

Interleukin-10 (IL-10) is an important regulatory cytokine required to control allergy and asthma. IL-10-mediated regulation of T cell-mediated responses was previously thought to occur indirectly via antigen-presenting cells. However, IL-10 can act directly on regulatory T cells and T helper type 17 (Th17) cells. In the context of allergy, it is therefore unclear whether IL-10 can directly regulate T helper type 2 (Th2) cells and whether this is an important regulatory axis during allergic responses. We sought to determine whether IL-10 signaling in CD4⁺ Th2 cells was an important mechanism of immune regulation during airway allergy. We demonstrate that IL-10 directly limits Th2 cell differentiation and survival in vitro and in vivo. Ablation of IL-10 signaling in Th2 cells led to enhanced Th2 cell survival and exacerbated pulmonary inflammation in a murine model of house dust mite allergy. Mechanistically, IL-10R signaling regulated the expression of several genes in Th2 cells, including granzyme B. Indeed, IL-10 increased granzyme B expression in Th2 cells and led to increased Th2 cell death, identifying an IL-10-regulated granzyme B axis in Th2 cells controlling Th2 cell survival. This study provides clear evidence that IL-10 exerts direct effects on Th2 cells, regulating the survival of Th2 cells and severity of Th2-mediated allergic airway inflammation.     

The biological role and potential therapeutic application of interleukin 7

Interleukin (IL)-7 is a pleiotropic, non-redundant cytokine necessary for the development of B and T lymphocytes, in particular gammadelta T cell receptor-positive cell differentiation. The cytokine can function as a cofactor during myelopoiesis and the generation of cytotoxic T cells and natural killer cells, can activate monocytes/macrophages, and support the survival of mature T cells. A role for IL-7 in promoting the formation of Peyer's patch anlage has also been demonstrated. IL-7 is constitutively expressed in the thymus, bone marrow stromal cells, epithelial and dendritic cells, keratinocytes, as well as in fetal and adult liver. IL-7 acts on various cells through its receptor (IL-7R), a heterodimer consisting of an alpha chain (CD127) that specifically binds IL-7 and a common gamma(c) chain (CD132) shared by other cytokine receptors. The receptor is expressed on bone marrow progenitor cells, lymphoid T and B precursors, and mature T cells. IL-7 activity towards murine endothelial cells has been recently described. The presence of IL-7R on human endothelial cells has also been demonstrated. Several therapeutic applications of recombinant IL-7 have been proposed. These have focused on the enhancement of lymphopoiesis, promotion of stem cell engraftment, and the anti-tumor activity of the cytokine.     

IL-10-induced gp130 expression in mouse mast cells permits IL-6 trans-signaling

It is reported that human and mouse mast cells express the IL-27R, which consists of WSX-1 (the IL-27Rα subunit) and the signal-transducing subunit gp130. Although it has been proposed that IL-27 may negatively regulate mast cell-dependent, immediate hypersensitivity responses directly, this has yet to be examined specifically. We found that mouse BMMC and primary peritoneal mast cells are unresponsive to IL-27. Consistent with this, gp130 protein in resting BMMC was not on the cell surface to a measurable degree but was found intracellularly, and data are consistent with incompletely processed N-linked glycosylation. Furthermore, BMMC constitutively expressed SOCS3, a major negative regulator of gp130 signaling. However, BMMC stimulation with IL-10 and consequential STAT3 activation increased gp130 expression, which resulted in a functional gp130 receptor on the BMMC cell surface. IL-10 has not been previously shown to regulate gp130 expression, which on the BMMC surface, permitted IL-6 trans-signaling, found to increase survival under limiting conditions and enhance IL-13 and TNF-α secretion. This study identifies factors that regulate mouse mast cell gp130 expression and signaling and makes conspicuous the limitations of using cultured mouse mast cells to study the effects of the IL-6/IL-12 cytokine family on mast cell biology.     

Low expression of CD40 and B7 on macrophages infiltrating UV-exposed human skin; role in IL-2Rα− T cell activation

After UV exposure of skin, epidermal Langerhans cells (LC) are depleted, whereas CD11b⁺ CD36⁺ CD1a⁻ monocytes/macrophages (UV-Mϕ) infiltrate. Different immunological outcomes in vivo are mediated by LC (sensitization) and UV-Mϕ (tolerance) which may be related to the distinct T cell activation states that these antigen-presenting cells (APC) induce. We previously demonstrated that CD4⁺ T lymphocytes activated by UV-Mϕ are, in contrast to LC-activated T cells, IL-2Rα deficient, and we hypothesize that this differential T cell activation is related to differences in co-stimulatory molecules between UV-Mϕ and LC. Using four-color flow cytometry, we found a reduced capacity to up-regulate expression of the important co-stimulatory molecules CD40, B7-1 and B7-2 by UV-Mϕ relative to LC. This alteration in co-stimulatory molecule expression was selective, because UV-Mϕ express equal levels of ICAM-1 and ICAM-3, and increased levels of LFA-1, relative to LC. After bidirectional signaling with T cells during alloantigen presentation, UV-Mϕ still exhibited less CD40 and B7-1 than LC. Addition of IFN-γ induced CD40 and B7-1 expression on UV-Mϕ and restored IL-2Rα expression on UV-Mϕ-activated T cells but had no effect on IL-2Rα on resting or LC-activated T cells. The restoration of IL-2Rα expression on UV-Mϕ-activated T cells by IFN-γ was inhibited (67 %, p = 0.005) by addition of neutralizing anti-CD40. Therefore, differences in co-stimulatory molecule expression, in particular CD40, on UV-Mϕ and LC are critical in determining the distinct T cell activation induced by these APC.     

Regulation of the IL-12/IL-12R axis: a critical step in T-helper cell differentiation and effector function

Summary: Interleukin (IL)-12 is required for the development of T-helper (Th)1 cells, which have been shown to be important for protective cell-mediated immune responses against a variety of intracellular pathogens. Recent studies have clarified the sources and the regulation ofIL-12 production leading to Th1 development against microbes. Expression of IL-12R is necessary for maintaining IL-12 responsiveness and controlling Thl lineage commitment. Advances in this area have included a broader understanding of the factors involved in the regulation of the IL-12Rβ2 signaling component. Expression of this receptor subunit in humans is critically influenced by IL-12 and type I interferons. IL-12 signaling results in STAT4 activation and interferon (IFN)-γ production. Recent evidence suggests that IL-12 also modulates a number of genes involved in leukocyte trafficking. Thus, IL-12 is not only an important proinflammatory cytokine, which induces production of IFN-γ and subsequent activation of phago-cytic cells but also plays a major role in regulating the migration and proper positioning of effector cells.