Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus

Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism（s） of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I （myriocin）. FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] by sphingosine kinase 2 in vivo. （S）-FTY720-P acting as a potent agonist of S1P receptor type 1 （S1P1）, induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite （S）-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.     

The Common γc-Cytokines and Transplantation Tolerance

Transplant rejection, like tolerance, is a T cell-dependent event.There is compelling evidence to suggest that induction of transplant tolerance is an actively learned process in which T cells need to engage with the alloantigens in order to learn to tolerate the allograft. A family of cytokines whose receptors use the same IL-2 receptor γc chain (also called the common γc) plays an important role in regulating multiple aspects of the allograft response (i.e. rejection vs. tolerance). It is undeniable that γc cytokines can drive clonal expansion and effector maturation of alloreactive T cells, and therefore, targeting such cytokines or their receptor components remains an attractive way of blocking transplant rejection. However, we just started to appreciate that γc cytokines also regulate the acquisition of transplant tolerance via programming activated T cells for apoptotic cell death and via guiding the evolution of regulatory T cells. Thus, understanding precisely the role of γc cytokines in regulating T cell homeostasis and T cell regulation is critically important in the induction of transplant tolerance.     

Epithelial cell apoptosis and lung remodeling

Lung epithelium is the primary site of lung damage in various lung diseases. Epithelial cell apoptosis has been considered to be initial event in various lung diseases. Apoptosis signaling is classically composed of two principle pathways. One is a direct pathway from death receptor ligation to caspase cascade activation and cell death. The other pathway triggered by stresses such as drugs, radiation, infectious agents and reactive oxygen species is mediated by mitochondria. Endoplasmic reticulum has also been shown to be the organeile to mediate apoptosis. Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation, cytokine production, activation of coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis. Epithelial and mesenchymai interaction plays important roles in these processes. Further understanding of apoptosis signaling and its regulation by novel strategies may lead to effective treatments against various lung diseases. We review the recent advances in the understanding of apoptosis signaling and discuss the involvement of apoptosis in lung remodeling. Cellular ＆ Molecular Immunology.     

Global Gene Expression Profiling in Interleukin-12-Induced Activation of CD8^＋ Cytotoxic T Lymphocytes against MouseMammary Carcinoma

Interleukin-12(IL-12) is a critical cytokine representing the link between the cellular and humoral branches ofhost immune defense apparatus.IL-12-induced cytotoxic lymphocyte(CTL) development is a centralmechanism in immune responses against intracellular infectious agents as well as malignant growth.However,the molecular basis of tumor-specific CTL responses mediated by IL-12 remains poorly defined.In this study,we addressed this issue in a comprehensive manner to probe into IL-12-induced anti-tumor responses by globalgene expression profiling of mRNA expression in CD8~+ T cells in a transplantable syngeneic mouse mammarycarcinoma model treated or not with recombinant IL-12.A strong tumor regression was induced by the IL-12treatment.An introspection of differential gene expression at an early stage of the IL-12-initiated CTLactivation reveals interesting genes and molecular pathways that may account for the marked tumor regression,and is likely to provide a rich source of potential targets for further research and development of effectivetherapeutic modalities.Cellular & Molecular Immunology.2004;1(5):357-366.     

Recent advances of cluster of differentiation 74 in cancer

Cluster of differentiation 74(CD74) performs multiple roles in B cells,T cells,and antigen-presenting cells within the immune system; it also participates in major histocompatibility complex class Ⅱ-restricted antigen presentation and inflammation. Recently,a role for CD74 in carcinogenesis has been described. CD74 promotes cell proliferation and motility and prevents cell death in a macrophage migration inhibitory factordependent manner. Its roles as an accessory signal receptor on the cell surface and the ability to interact with other signaling molecules make CD74 an attractive therapeutic target for the treatment of cancer. This review focuses on the original role of CD74 in the immune system and its emerging tumor-related functions. First,the structure of CD74 will be summarized. Second,the current understandings about the expression,cellular localization,molecular mechanisms and signaling pathways of CD74 in immunity and cancerwill be reviewed. Third,the examples that suggest CD74 is a promising molecular therapeutic target are reviewed and discussed. Although the safety and efficacy of CD74-targeted strategies are under development,deeply understanding of the regulation of CD74 will hold promise for the use of CD74 as a therapeutic target and may develop the CD74-targeted therapeutic agents such as neutralized antibody and compounds.     

Future directions of clinical laboratory evaluation ol pregnancy

In recent years, our understanding of how the immune system interacts with the developing fetus and placenta has greatly expanded. There are many laboratories that provide tests for diagnosis of pregnancy outcome in women who have recurrent pregnancy loss （RPL） or pre-eclampsia. These tests are based on the premise that immune response to the fetus is equivalent to the adaptive immune response to a transplant. New understanding leads to the concept that the activated innate response is vital for pregnancy and this can result in more effective testing and treatment to prevent an abnormal pregnancy in the future. We describe here only three such areas for future testing： one area involves sperm and semen and factors necessary for successful fertilization; another area would determine conditions for production of growth factors necessary for implantation in the uterus; finally, the last area would be to determine conditions necessary for the vascularization of the placenta and growing fetus by activated natural killer （NK） cells （combinations of killer cell immunoglobulin-like receptor （KIR） family genes with HLA-C haplotypes） that lead to capability of secreting angiogenic growth factors. These areas are novel but understanding their role in pregnancy can lead to insight into how to maintain and treat pregnancies with complicating factors.     

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer （NK） cells and CD8^＋T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor （TNF） and TNF receptor pathway. We discussed three models of possible molecular interaction between lytic molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis. Cellular ＆ Molecular Immunology.     

Targeting TLR4/MAPKs signaling pathway:A better option for therapeutic inhibition of atherosclerosis

Cardiovascular diseases, especially atherosclerosis, found to be the dreadful diseases worldwide. There are diverse pathways associated with the progression of atherosclerosis. One of the important signaling pathways to target atherosclerotic plaque rupture is toll-like receptor 4(TLR4) Pathway. Several studies are available for illustrating the role of TLR4 in health and diseases. Different types of immune cell are activated in atherosclerosis but primary cells that are activated by the TLR4 signaling are macrophages and endothelial cells. Mechanisms by which macrophages uptake lipids are diverse and it is very important to target signaling pathway responsible for controlling foam cell formation. The process of macrophages transformed foam cell formation is the critical event in progression of atherosclerotic lesion and TLR4 found to have actively participate in the event through mitogen activated protein kinases(MAPKs) activation. The activation of MAPKs signaling pathway leads to the accumulation of cholesterol in the macrophages and also contribute to the dissociation of IκB and the nuclear translocation of nuclear factor kappalight-chain-enhancer of activated B cells(NF-κB) p65 subunit, thereby activating key inflammatory cascadeactivation by MAPKs/NF-κB signaling pathway to induce toxicity by activating different inflammatory parameters. Hence, the review focussed on exploring the role of TLR4/MAPKs signaling pathway for the therapeutic inhibition of atherosclerosis.     

Pharmacological advantages of melatonin in immunosenescence by improving activity of T lymphocytes

Melatonin plays a critical role in regulating photoperiodic signals and has recently been shown to decrease immunosenescence with age.In this study,we examined whether melatonin activates T lymphocytes as major adaptive immune cells in in vitro and in vivo models.Splenocytes,CD4~+,and nave CD4 T lymphocytes were isolated from the spleen of BALB/c mice and the cell population patterns and mRNA profiles associated with T cell activation(CD28 and p21) and the melatonin receptor(MT1A and MT1B) were assessed.The T cell activationrelated proteins Ki67 and Bcl2 were also evaluated to confirm the relationship between gene and protein levels.Our data clearly revealed that CD28,p21,MT1 A,and MT1 B mRNA were highly expressed in the presence of melatonin.Co-culture of CD4~+ T lymphocyte and peritoneal macrophage 7 days after melatonin administration to young and aged mice significantly increased APRIL mRNA,suggesting induction or maintenance of T lymphocyte responses.We also found that the intracellular amount of Ki67 and Bcl2 proteins were significantly upregulated in aged CD4~+ T lymphocytes,suggesting enhancing T cell proliferation and ling-term maintenance of memory T cells.Taken together,we conclude that melatonin supplementation may enhance immunity in aged individuals by upregulating immunosenescence indices in association with T lymphocytes and may be an attractive pharmacological candidate for aged and immunocompromised individuals.     

The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation

The tumor necrosis factor (TNF) receptor superfamily member herpesvirus entry mediator (HVEM) (TNFRSF14) regulates T-cell immune responses by activating both inflammatory and inhibitory signaling pathways. HVEM acts as both a receptor for the canonical TNF-related ligands, LIGHT [lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed on T lymphocytes] and lymphotoxin-α, and as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules. The ability of HVEM to interact with multiple ligands in distinct configurations creates a functionally diverse set of intrinsic and bidirectional signaling pathways that control both inflammatory and inhibitory responses. The HVEM system is integrated into the larger LTβR and TNFR network through extensive shared ligand and receptor usage. Experimental mouse models and human diseases indicate that dysregulation of HVEM network may contribute to autoimmune pathogenesis, making it an attractive target for drug intervention.     

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.     

Pre-B cell receptor signaling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway.

B lymphocyte development is regulated at multiple checkpoints, mediated by signals originating both inside and outside the cell. Two signaling pathways known to be essential in this process are interleukin-7 (IL-7) and the pre-B cell receptor (pBCR). We have shown previously that these signaling pathways intersect functionally. Specifically, response to low concentrations of IL-7 requires pBCR expression. In this report, we identify the ERK/MAP kinase pathway as a key regulatory component of this response. We propose a molecular mechanism for the selective expansion of pBCR(+) precursors and for the culling of inappropriately rearranged pro-B cells.     

Genetic approaches to tyrosine kinase signaling pathways in the immune system

The development of a productive immune response requires the carefully coordinated activation of lymphocytes through their cell-surface antigen receptors, surface immunoglobulin (Ig) on B cells and the T cell receptor (TCR) on T cells. Studies of mutant cell lines, gene-targeted mice and humans with inherited immunodeficiencies have demonstrated that tyrosine kinases are critical components of lymphocyte antigen-receptor-signaling pathways. Our laboratory is interested in the mechanisms by which modulation of signaling pathways involving tyrosine kinases and related signaling molecules can influence cell function and development. We have concentrated our attention on the genetic and biochemical dissection of signaling pathways in the immune system, and how altering these pathways can change responses to infectious disease. As a model system, we are examining the Tec family kinases and their roles in T lymphocyte development and function.     

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.     

Puppet masters of B-cell progenitor acute lymphoblastic leukemia: The preB cell receptor and the interleukin 7 receptor α

B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is enriched for a preB cell phenotype, hinting at a specific vulnerability of this cell stage. Two signaling pathways via the preB cell receptor (preBCR) and the interleukin 7 receptor α (IL-7Rα) chain govern the balance between differentiation and proliferation at this stage and both receptor pathways are routinely altered in human BCP-ALL. Here, we review the immunobiology of both the preBCR as well as the IL-7Rα and analyze the human BCP-ALL spectrum in the light of these signaling complexes. Finally, we present a terminology for preBCR signaling modules that distinguishes a pro-proliferative “phase-I” module from a pro-differentiative “phase-II” module. This terminology might serve as a framework to better address shared oncogenic mechanics of preB cell stage BCP-ALL.     

Notch signaling in lymphocyte development

Cytokine and antigen receptor signals play well-characterized roles in promoting the survival and maturation of T and B lymphocyte progenitors through sequential developmental stages. Emerging studies suggest equally important roles for more ancient signaling pathways that evolved prior to the adaptive immune system in jawed vertebrates. In particular, there are at least two essential functions for the highly conserved Notch signaling pathway in lymphocyte development. First, Notch signals are essential for the development of T cell progenitors in the thymus and intestinal epithelium. Second, Notch signals are required to suppress B cell development in the thymus. This review will focus on focus on recent advances in our understanding of how Notch signaling regulates this developmental switch, as well as how Notch might regulate subsequent survival and cell fate decisions in developing T cells.     

The role of cytokine receptor signaling in lymphocyte development.

Cytokine receptor signaling plays an essential role in the early stages of lymphocyte development. Signals through various cytokine receptors - such as c-kit, flt3/flk2, CXCR4, the IL-7 receptor and the IL-15 receptor - are known to promote the expansion and survival of uncommitted progenitor cells as well as their migration to the appropriate microenvironment and subsequent differentiation into B, T or natural killer cells. The recent generation of mice deficient in one or more of these signaling pathways has revealed which cytokines play unique and/or redundant roles in each of these lymphocyte lineages during this developmental process.