While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a subset (...) of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

A model is proposed which implicates molecular recognition systems as the major controlling factors in life cycle expression. It is envisaged that such systems are important in immune functioning and catabolic, metabolic molecule recognition at both inter- and intea-cellular level. These recognition systems have the following characteristics: Specific recognition molecules , e.g. vertebrate antibodies, invertebrate agglutinins and plant agglutinins may recognise specific substances, e.g. antigens, catabolic and metabolic molecules. The range of possible recognisable substances is very wide and variable. The (...) recognisers may themselves be recognised by other recognisers. Recognisers are usually produced in large amounts only on presentation of the appropriate recognisable molecule. The progressive introduction of new recognisable molecules increases the recogniser interaction, this interaction causing depression of some recogniser types and facilitation of other types among which may be recognisers specific for self components . Low juvenile viability is associated with a restricted range of available recognisers, high adult viability with increasing recogniser range and some auto-immunity/immune depression, senescence with a wide range of available recognisers and extensive auto-immunity/immune depression.Life cycle patterns and their control are discussed. It is suggested control mechanisms may include: Dietary restriction and in some periods complete nutritional abstinence. Specific recogniser depression, genes implicated here are the various antigens found on cell surfaces, in the serum and in various body fluids of vertebrates, e.g. ABO, MNSs, P, Rh, Le and other blood groups, the ABO and Le secretor antigens and the HL-A antigens. In addition the immune response and mixed lymphocyte culture loci are implicated. Finally life cycle control is discussed with relation to sexual selection. (shrink)

The T lymphocyte receptor for antigen, which operates in conjunction with gene products of the major histocompatibility complex (MHC), is a molecular complex comprised of five polypeptide chains. Both the 49 kDa alpha and 43 kDa beta chains are immunoglobulin‐like and thus contain variable domains responsible for ligand binding. In contrast, the 20–25 kDa T3 gamma, delta and epsilon chains are monomorphic structures presumably involved in transmembrane signalling. The alpha and beta subunits are disulfide bonded to each other and held (...) in noncovalent association with the T3 chains. T3‐Ti receptor crosslinking leads to conformational modification of a second T lineage specific molecule, termed the 50 kDa T11 structure which in turn leads to protein kinase C activation, elevation in intracytoplasmic free calcium and Na+/H+ antiport stimulation. (shrink)

Adapter molecules in a variety of signal transduction systems link receptors to a limited number of commonly used downstream signaling pathways. During T‐cell development and mature T‐cell effector function, a multichain receptor (the pre‐T‐cell antigen receptor or the T‐cell antigen receptor) activates several protein tyrosine kinases. Receptor and kinase activation is linked to distal signaling pathways (PLC‐γ1 activation, Ca2+ influx, PKC activation and Ras/Erk activation) via the adapter protein LAT (Linker for Activation of T cells). Structure/function studies of LAT including (...) expression of selected LAT point mutations in vivo reveals that these multiple pathways are integrated at the level of the LAT adapter. These studies suggest that similar levels of control may be found in other systems where adapter molecules are known to have important functions. BioEssays 26:61–67, 2004. Published 2003 Wiley Periodicals, Inc. (shrink)

Binding of antigen or lectin to the surface of a T lymphocyte initiates a complex sequence of events which result in both T cell proliferation and the acquisition of immunologic functions. This complex sequence of events is most likely programmed and precisely timed by a series of contingent gene activations in which one member of this series activates the next. The two most obvious examples of these stages are the set of genes activated when antigen interacts with the antigen receptor (...) and the set of genes activated when IL‐2 interacts with its receptor. However, it is likely that several other parallel pathways of gene activation are necessary to bring about T‐cell division. An example would be the antigen‐induced activation of the c‐myc gene, which in turn is likely to be involved in regulating an additional group of genes not directly controlled by either IL‐2 or antigen. A fundamental understanding of T‐lymphocyte activation necessitates identification of the factors involved in initiating each of these contingent levels of gene activation. (shrink)

The differentiation of T Lymphocytes within the thymus is an important biological phenomenon during wich these cell acquire their functions to further control the immune system. Numerous experiments under various conditions have been devised to understand the different mechanisms involved in this complex process. Nevertheless, interpretation of these experiments lead to still contradictory debatable hypotheses. Modelisation of this process through classical simulation methods cannot be envisaged because they are not adapted to modifications of the model structure, which is the (...) point of interest. For these reasons, we proposed a new approach of automatic search for model. The program consists of four independent connected modules : The generator produces model, based on the rationale of formal grammars. Protocol and experimental data are stored in a set of experiments. The simulator using a protocol and a model provides simulated results. Finally, the supervisor by comparing simulated results and experimental data, adapts the model parameters to increase their fit and either chooses a new experiment to explore, or modifies the model structure. Change of the model structure is performed among still unexplored models according to their promise level, which is iteratively evaluated relatively to previously explored models through a proposed model distance. The generator is written in Prolog and the other modules in C++. The architecture of the program allows us to modify or complete a module without changing anything in the other modules. As a consequence, the proposed modeling approach conceived to study T lymphocyte differentiation within the thymus remains independent of this biological phenomenon and can be applied to other biological problems. (shrink)

The differentiation of T lymphocytes, the cells that are responsible for cell‐mediated immunity, takes place within the thymus, but details of the developmental pathway have long been obscure. Although distinct subpopulations of thymocytes had been characterized, they acted like separate developmental streams rather than sequential differentiation stages. Recently, a minor subgroup of thymocytes representing an earlier blast population has been identified, offering the hope that the key developmental events will be discerned by focus on this new population of precursor (...) cells. (shrink)

Tumor‐infiltrating lymphocyte (TIL) therapy is a promising approach for treating refractory or advanced solid cancers by using autologous TILs harvested from cancer tissues. Despite the heterogeneity of cancer, TIL therapy can potentially produce a positive therapeutic response, including complete remission.After decades of research on lymphocyte functions, culture/expansion methods, therapeutic protocols, and multiple clinical trials, TIL therapy has finally reached a stage where it can be formally approved for clinical use.TIL therapy is expected to hold a unique position among anti‐cancer therapeutic (...) options as a standard intervention. To successfully introduce TIL therapy into clinical settings, there is a need to expand therapeutic indications and set up the best protocols for cancer tissue sampling and manufacturing, and related clinical trials. Moreover, studies on next‐generation TIL therapy have already begun, and post‐approval real‐world data will promote and support further research. (shrink)

T lymphocyte recognition of foreign antigens and migration throughout the body require the regulated adhesion of lymphocytes to diverse types of cells and to the extracellular matrix. The lymphocyte adhesion ‘receptor’ LFA‐1, a member of the integrin family, interacts with ICAM‐1 and other counter‐receptors to mediate adhesion. The LFA‐1/ICAM‐1 interaction is regulated by signals transmitted from the cytoplasm to the extracellular space. Conversely, LFA‐1 transmits signals from the extracellular space to the cytoplasm to regulate T lymphocyte activation. The observed (...) properties of LFA‐1 and related adhesion ‘receptors’ are incorporated into a general model for adhesion during immune surveillance and recognition of foreign antigens. (shrink)

The development of T cells and B cells from pluripotent hematopoietic precursors occurs through a stepwise narrowing of developmental potential that ends in lineage commitment. During this process, lineage-specific genes are activated asynchronously, and lineage-inappropriate genes, although initially expressed, are asynchronously turned off. These complex gene expression events are the outcome of the changes in expression of multiple transcription factors with partially overlapping roles in early lymphocyte and myeloid cell development. Key transcription factors promoting B-cell development and candidates for this (...) role in T-cell development are discussed in terms of their possible modes of action in fate determination. We discuss how a robust, stable, cell-type–specific gene expression pattern may be established in part by the interplay between endogenous transcription factors and signals transduced by cytokine receptors, and in part by the network of effects of particular transcription factors on each other. BioEssays 21:726–742, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

An alternative antigen receptor, named the variable lymphocyte receptor (VLR), was first identified in lampreys in 2004. Since then, the mechanism of VLR diversification via somatic gene assembly and the function of VLR‐expressing lymphocytes have been the subject of much research. VLRs comprise leucine‐rich repeat (LRR) motifs and are found only in the most phylogenetically distant vertebrates from mammals, lampreys, and hagfish. Previous reports showed that VLRA and VLRB are reciprocally expressed by lymphocytes that resemble T‐ and B (...) cells; however, more recent reports show that another VLR, VLRC, is expressed on a third lymphocyte lineage, which may be equivalent to γδ T cells. The existence of three major lymphocyte lineages – one B‐cell‐like and two T‐cell‐like – and their development in lampreys, parallels the mammalian adaptive immune system. This suggests that these three cell lineages were present in the common vertebrate ancestor approximately 500 million years ago. (shrink)

T‐lymphocyte recognition, activation and function involve anumber of T‐cell‐specific surface proteins in addition to the receptor for antigen. The structure, function and genetic analysis of four of these T‐cell differentiation antigens are discussed.

T lymphocytes circulate continually throughout the peripheral lymphoid organs, where they scrutinize the surface of cells to detect the presence of nonself protein fragments. During the last years, many facets of T-cell function have been unravelled. After being bound by major histocompatibility complex (MHC) molecules, peptides derived from nonself as well as from self proteins are delivered to the cell surface. A few copies of a nonself peptide “presented” at the cell surface in the context of an MHC molecule (...) can be detected by specific T cells, and suffice to trigger T-cell activation. This paper reviews the requirements imposed on T cells to fulfill this exquisite sensitivity. BioEssays 20:412–422, 1998.© 1998 John Wiley & Sons Inc. (shrink)

T lymphocytes circulate continually throughout the peripheral lymphoid organs, where they scrutinize the surface of cells to detect the presence of nonself protein fragments. During the last years, many facets of T-cell function have been unravelled. After being bound by major histocompatibility complex (MHC) molecules, peptides derived from nonself as well as from self proteins are delivered to the cell surface. A few copies of a nonself peptide “presented” at the cell surface in the context of an MHC molecule (...) can be detected by specific T cells, and suffice to trigger T-cell activation. This paper reviews the requirements imposed on T cells to fulfill this exquisite sensitivity. BioEssays 20:412–422, 1998.© 1998 John Wiley & Sons Inc. (shrink)

The immune surveillance theory postulates that spontaneous tumors are normally rejected by the immune system and appear only when they override host‐immune recognition and rejection mechanisms. The present mini‐review describes a spontaneous tumor system, the reticulum cell sarcomas (RCS) in SJL/J mice, that is dependent on host tumor‐specific immune lymphocytes for growth. This continuous tumor‐specific response results in tumor progression and death of the host. This tumor system contradicts the basic concept of immune surveillance. We propose as an explanation (...) that some highly antigenic tumors, like the RCS, may have evolved in a non‐autonomous fashion but, nevertheless, have lost regulatory controls of cell proliferation. In the RCS system, the tumor expresses Class II MHC I‐E like specificities that are not expressed on the host cells and which selectively stimulate a subpopulation of I‐E specific T cells, the Vβ17a+ clonotype, leading to their expansion and continuous nurturing of the tumor via secreted lymphokines. This neoantigenic stimulation bypasses the tumor regulatory response that might have resulted if the tumor had not expressed neo‐antigens. Furthermore, passive administration of anti‐clonotypic antibody to tumor‐bearing mice results in tumor regression and long‐term survival through removal of the tumor reactive T cells. Thus, in this tumor system, immunosuppressive treatments are the prescription for tumor rejection. (shrink)

T‐bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells. Recent genome‐wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the (...) epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion. We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T‐bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking. (shrink)

Activation of resting T lymphocytes through the T cell antigen receptor complex is initiated by critical phosphorylation and dephosphorylation events that regulate the function and interaction of a number of signaling molecules. Key elements in these reactions are members of the Src, Syk and Csk families of protein tyrosine kinases (PTKs) and the phosphotyrosine phosphatases (PTPases) that regulate and/or counteract them, such as CD45. The PTKs can autophosphorylate and phosphorylate each other at multiple sites and, as the result of (...) these interactions, they are induced to phosphorylate other cellular proteins. These phosphorylation events lead to modulation of enzymatic activities and/or serve as binding sites for other signaling molecules having phosphotyrosine‐binding Src homology 2 (SH2) domains. As a result, these proteins translocate to the receptor complexes and are juxtaposed to the kinases that phosphorylate them. Some of the SH2‐domain‐containing polypeptides lack enzymatic activities and, instead, serve as adapter molecules that couple the signal to downstream effectors, such as regulators of the Ras proteins, and further into serine/threonine‐specific protein kinase cascades. Through largely unknown steps these reactions lead to the transcription of previously silent genes, activation of lymphocyte effector functions, progression through the cell cycle and cell proliferation. (shrink)

Experiments with cell lines have unveiled the implication of the Rho/Rac family of GTPases in cytoskeletal organization, mitogenesis, and cell migration. However, there have not been adequate animal models to investigate the role of these proteins in more physiological settings. This scenario has changed recently in the case of the T‐cell lineage after the generation of animal models for Rho/Rac family members, their regulators, and effectors. These studies have revealed the implication of these GTPases on multiple regulatory layers of T‐cells, (...) including the coordination of cytoskeletal change, activation of kinase cascades, stimulation of calcium fluxes, and the induction of gene expression. These pathways affect the transition of different T‐cell maturation stages, the positive/negative selection of thymocytes, T‐cell responses to antigens, and the homeostasis of peripheral T‐lymphocytes. Moreover, these animals have revealed interesting cross‐talks between Rho/Rac pathways and other signal transduction routes that participate in lymphocyte responses. BioEssays 24:602–612, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Most lymphocytes of the T cell lineage develop along the CD4/CD8 pathway and express antigen receptors on their surfaces consisting of clonotypic αβ chains associated with invariant CD3‐γδε components and ζ chains, collectively referred to as the T cell antigen receptor complex (TCR). Expression of the TCR complex is dynamically regulated during T cell development, with immature CD4+CD8+ thymocytes expressing only 10% of the number of αβ TCR complexes on their surfaces expressed by mature CD4+ and CD8+ T cells. (...) Recent evidence demonstrates that low surface TCR density on CD4+CD8+ thymocytes results from the limited survival of a single TCR component within the ER, the TCRα chain, which has a half life of only 15 minutes in immature thymocytes, compared to >75 minutes in mature T cells. Instability of TCRα proteins in immature CD4+CD8+ thymocytes represents a novel mechanism by which expression of the multisubunit TCR complex is quantitatively regulated during T cell development. In the current review we discuss our recent findings concerning the assembly, intracellular transport, and expression of αβ TCR complexes in CD4+CD8+ thymocytes and comment on the functional significance of TCRα instability during T cell development. (shrink)

In this book, T. L. Short places the notorious difficulties of Peirce's important writings in a more productive light, arguing that he wrote philosophy as a scientist, by framing conjectures intended to be refined or superseded in the inquiries they initiate. He argues also that Peirce held that the methods and metaphysics of modern science are amended as inquiry progresses, making metaphysics a branch of empirical knowledge. Additionally, Short shows that Peirce's scientific work expanded empiricism on empirical grounds, grounding his (...) phenomenology and subverting the fact/value dichotomy, and that he understood statistical explanations in nineteenth-century science as reintroducing the idea of final causation, now made empirical. Those innovations underlie Peirce's late ideas of a normative science and of philosophy as a branch of science. Short's rich and original study shows us how to read Peirce's writings and why they are worth reading. (shrink)

T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αβ and γδ receptors, T cells are mainly divided into αβ and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well‐characterized and different developmental processes. N6‐Methyladenosine (m6A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Recently, we have demonstrated (...) that the depletion of m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αβ T cells, indicating a checkpoint role of ALKBH5 and m6A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m6A modification. In this review, we mainly summarize the potential regulation between m6A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development. (shrink)

A Greek English Lexicon of the New Testament, being Grimm's Wilke's Clavis Novi Testamenti. Translated, Revised and Enlarged by Joseph Henry Thayer, D.D., Bussey Professor of New Testament Criticism and Interpretation in the Divinity School of Harvard University. Edinburgh, T. and T. Clark. 1886. 4to. pp. 726. 36s.Biblico Theological Lexicon to New Testament Greek. by Hermann Cremer, D.D., Professor of Theology in the University of Greifswald. Third English Edition. With Supplement. Translated from the latest German Edition by William Uewick, M.A. (...) Edinburgh, T. and T. Clark. 1886. 4to. pp. 943. 38s. (shrink)

This text is designed to help students construct and evaluate arguments.

This article discusses textually problematic passages in Catullus 63, a particularly corrupt poem from a particularly corrupt manuscript tradition. It proposes new conjectures and revives several old ones. Throughout there are notes on punctuation, conjecture attribution and an analysis of the structure of Attis’ lament.

From Socrates To Satre presents a rousing and readable introduction to the lives, and times of the great philosophers. This thought-provoking book takes us from the inception of Western society Plato's Athens to today when the commanding power of Marxism has captured one third of the world. T.Z. Lavine, Elton Professor of Philosophy at George Washington University, makes philosophy come alive with astonishing clarity to give us a deeper, more meaningful understanding of ourselves and our times. From Socrates To Satire (...) discusses Western philosophers in terms of the historical and intellectual environment which influenced them, and it connects their lasting ideas to the public and private choices we face in America today From Socrates To Satre formed the basis for the PBS television series of the same name. (shrink)

This essay argues that normative judgments, in general, and moral judgments, in particular, are "truth apt" and can be objects of belief. Other main claims are: judgments about reasons, if interpreted as true, do not have metaphysical implications that are incompatible with a scientific view of the world. Two kinds of normative claims should be distinguished: substantive claims about what reasons people have and structural claims about what attitudes people must have insofar as they are rational. Employing this distinction, the (...) practical significance of substantive normative judgments is explained, and critical analysis of expressivist and Kantian views on this question is offered. (shrink)

The scientific transformation of the hermeneutic art has been the common goal for the various formalist-structuralist programs of interpretation that have dominated human studies in our century - such as New Criticism in literary analysis, the formalist programs in art history and musicology, the Gestalt and Freudian psychology, structuralism in linguistics and anthropology, etc. In this volume, these formalist-structuralist programs shall be called structural programs of interpretation in Europe and America.

The present piece is a reply to G. Hoffmann on my infallibilist view of self-knowledge. Contra Hoffmann, it is argued that the view does not preclude a Quinean epistemology, wherein every belief is subject to empirical revision.