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 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)

Somatic diversification of antigen receptor genes depends on the activity of enzymes whose homologs participate in a mutagenic DNA repair in unicellular species. Indeed, by engaging error-prone polymerases, gap filling molecules and altered mismatch repair pathways, lymphocytes utilize conserved components of genomic stress response systems, which can already be found in bacteria and archaea. These ancient systems of mutagenesis and repair act to increase phenotypic diversity of microbial cell populations and operate to enhance their ability to produce fit variants during (...) stress. Coopted by lymphocytes, the ancient mutagenic processing systems retained their diversification functions instilling the adaptive immune cells with enhanced evolvability and defensive capacity to resist infection and damage. As reviewed here, the ubiquity and conserved character of specialized variation-generating mechanisms from bacteria to lymphocytes highlight the importance of these mechanisms for evolution of life in general. (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)

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 (...) class='Hi'>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)

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)

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)

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‐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.

Clonal expansion of T‐lymphocyte populations results from interactions of antigenic structures presented in combination with accessory cells (macrophages) and antibody recognition sites on the surface of T cells. The resulting activation of a membrane phospholipase C plays a crucial role in lymphocyte responses by releasing diglyceride and PIP3. The released diglyceride activates a cellular protein kinase C while PIP3 stimulates Ca2+ influx. Arachidonic acid released by the action of diglyceride lipase serves as substrate for the synthesis of (...) bioactive eicosanoids (prostaglandins and leukotrienes) which in turn modulate cellular adenyl and guanyl cyclases. The eicosanoids serve as both intra‐ and extra‐cellular signals for lymphocytes, regulating the production and expression of lymphokines and mediating the complex interactions between the monocyte‐macrophage components and helper and suppressor T cells.Aspirin and other anti‐inflammatory drugs stimulate mitogenesis by inhibiting production of the negative modulator prostaglandin E2 in accessory cells and by enhancing the production of the lymphokine 1L‐2 by producer T‐cells. (shrink)

Context: Immunity includes cognitive concepts: the organism is thought to specifically recognize foreign materials and develop a memory of these encounters. Vaccines are thought to work by enhancing this immunological memory. Lymphocytes are key cells and specific antibodies are key molecules in immune recognition. Antibodies are blood proteins called “immunoglobulins.” Spontaneously formed immunoglobulins are seen as “natural” antibodies to dietary components and commensal bacteria. Immune cognition is used simply as a didactic metaphor. Problem: Do the cognitive aspects of immunology stem (...) from the activities of cells and molecules, or are they ascribed by the immunologist operating as a human observer? (1) An immense variety of immunoglobulins may bind to the same antigen with different binding energies. It is the immunologist who arbitrates the boundary between those that are specific (and declared antibodies) and those that are not. Specific antibodies serve as functional labels pasted onto natural immunoglobulins, as if they were recognizing elements. Is this “arbitration” the true cognitive event ascribed to immunoglobulins and lymphocytes? (2) A major impasse exists between progress in experimental immunology and its translation into clinical results. A proper understanding of immunological activity demands a wider view of an organism’s biology and, also, of the interference of human observers in delineating experimental realities, such as the specificity of immune recognition. Maturana’s biology of cognition and language provides one such approach. Method: Use of Maturana’s biology of cognition and language concepts to describe immunological activity. Results: A whole new understanding of immunological activity is suggested. Implications: A major change in the way of seeing is proposed that may eventually help the translation of this knowledge into clinical results. Furthermore, the immune system may also become a proper model for cognitive analyses. (shrink)

Despite abundant evidence associating CD38 overexpression and CD4 T cell depletion in HIV infection, no causal relation has been investigated. To address this issue, a series of mechanisms are proposed, supported by evidence from different fields, by which CD38 overexpression can facilitate CD4 T cell depletion in HIV infection. According to this model, increased catalytic activity of CD38 may reduce CD4 T cells’ cytoplasmic nicotin‐amide adenine dinucleotide (NAD), leading to a chronic Warburg effect. This will reduce mitochondrial function. Simultaneously, CD38's (...) catalytic products ADPR and cADPR may be transported to the cytoplasm, where they can activate calcium channels and increase cytoplasmic Ca2+ concentrations, further altering mitochondrial integrity. These mechanisms will decrease the viability and regenerative capacity of CD4 T cells. These hypotheses can be tested experimentally, and might reveal novel therapeutic targets. (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)

Thy‐1 is a small glycoprotein of 110 amino acids which, folded in the characteristic structure of an immunoglobulin variable domain1, are anchored to the plasma membrane via a glycophosphatidylinositol (GPI) tail(2,3) (Fig. 1). It is a major component of the surface of various cell types, including neurons, at certain stages of their development (4). These qualities doubtlessly appeal to certain cognoscenti, but it is not clear why they would raise Thy‐1 to the status of a favourite molecule. Indeed, few scientists (...) readily admit to having a favourite. We study individual molecules because science is rooted in specific observations; but we do so in order to discover mechanisms of general importance. A molecule's appeal is dependent on its ability to reveal novel aspects of how nature works.Thy‐1 has been unusual in this respect. It was the first lymphocyte surface antigen shown to be restricted to a functional subset of lymphocytes (T cells in the mouse), a finding crucial to the development of cellular immunology(5); it was one of the first cell surface molecules to be sequenced and indicated the importance of immunoglobulin domains and GPI anchors as structural motifs(1–3); it has been pivotal in studies demonstrating that GPI‐anchored molecules are able to signal across the membrane they do not span(6, 7). Thy‐1 has revealed this much, however, with the charm of an adroit stripper: it has always promised glimpses of things more exciting than that displayed. In particular, the function of this molecule has never emerged.Our current work on Thy‐1 in the nervous system is, we believe, finally prizing this last secret into the open. It suggests that Thy‐1 on the neuronal surface interacts with one of the main glial types of adult brain, the astrocyte, to restrict axonal growth(8). There is no current consensus that astrocytes do regulate such growth, and this is the wider question we are addressing from the perspective of Thy‐1. At issue also is how to progress from knowing the nature of a molecule to defining its function. This task has already been achieved with molecules which were harder to characterise than Thy‐1. The problem is a classic Catch 22 situation: Thy‐1 has been readily characterised because it is small and abundant it is ten times more abundant than any other surface glycoprotein on rat thymocytes(9); but since there is so much of it, whatever it does it must do rather badly (or there would be no need to have so much of it!). Defining a function based on low activity or affinity is not trivial.Here I describe two aspects of work on Thy‐1. One is long completed ‐ the research which led to Thy‐1 being isolated and characterised ‐ and included because it demonstrates features which are still applicable to much research using a antibodies today. The other is our ongoing work on the nervous system, which is at that exciting early stage where hypotheses are formed, but the answers are still coming in. (shrink)

Phosphotyrosine phosphatases (PTPases) are the enzymes which remove phosphate groups from protein tyrosine residues. An enormous number of phosphatases have been cloned and sequenced during the past decade, many of which are expressed in haematopoietic cells. This review focuses on the biochemistry and cell biology of three phosphatases, the transmembrane CD45 and the cytosolic SH2‐domain‐containing PTPases SHP‐1 and SHP‐2, to illustrate the diverse ways in which PTPases regulate receptor signal transduction. The involvement of these and other PTPases has been demonstrated (...) in haematopoietic cell development, apoptosis, activation and non‐responsiveness. A common theme in the actions of many haematopoietic cell PTPases is the way in which they modulate the thresholds for receptor signalling, thereby regulating critical events in the positive and negative selection of lymphocytes. There is growing interest in haematopoietic PTPases and their associated regulatory proteins as targets for pharmaceutical intervention and in the involvement of these enzymes in human disease. (shrink)

Many functional glycoproteins are expressed on the lymphocyte cell surface. Some of them carry O-linked oligosaccharides (O-glycans), which are conjugated through serine or threonine residues. During various biological processes, including T-cell activation, a tetrasaccharide on the T-cell surface is dramatically converted to a branched hexasaccharide, called core2 O-glycan. The same structural change in O-glycans is also found on the lymphocytes from patients with immunodeficiency conditions such as Wiskott-Aldrich syndrome and AIDS. Several studies revealing the roles of core2 O-glycans (...) in immune responses show that this is a biologically significant change. In particular, core2 O-glycans expressed on the cell surface reduce cell–cell interactions, thereby regulating immune responses. Furthermore, core2 O-glycan is a key backbone structure in forming selectin ligands. Thus, O-linked oligosaccharides, in particular those containing core2 branches, play vital roles in immune responses and may play dual roles in certain situations. This review will summarize the results obtained from various studies investigating the roles of O-glycans in immunological processes. BioEssays 23:46–53, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

B cell activation is accompanied by metabolic adaptations to meet the increased energetic demands of proliferation. The metabolic composition of the microenvironment is known to change during a germinal center response, in inflamed tissue and to vary significantly between different organs. To sustain cellular homeostasis B cells need to be able to dynamically adapt to changes in their environment. An inability to take up and process available nutrients can result in impaired B cell growth and a diminished humoral immune (...) response. Furthermore, the metabolic microenvironment can affect B cell signaling and provide a means to avoid aberrant proliferation or modulate B cell function. Thus, a better understanding of the intricate interplay between cell signaling and metabolism could provide novel insight into how B cell function is regulated and have implications for the development of vaccines or treatment of autoimmune disorders and B cell derived malignancies. Throughout their lifespan, B cells are exposed to different metabolic environments. Signaling pathways regulating cellular responses to metabolic stress not only help to maintain B cell viability and to facilitate cellular functions but may also play an important role in preventing excessive proliferation and malignant transformation. (shrink)

In the development of the immune response, the dendritic cell subset of leukocytes plays a key role in enhancing immunogenicity. Dendritic cells can pick up antigens in the tissues and move to lymphoid organs, through which T cells continually recirculate. It is proposed that dendritic cells at these sites express functions which have beenidentified in tissue culture models. These involve efficient binding to antigen‐specific T lymphocytes, as well as the induction of the lymphokines and growth factor receptors required for immunity. (...) The dendritic cell system, apparently under the control of cytokines, is a sentinel designed to signal T cells that a significant antigen burden is present, and to generate the activated T lymphoblasts that interact with many other cell types to bring about an immune response. (shrink)

One of the characteristics of all somatic cells is a finite life span. Cells may proliferate until they reach a point after which, although they are metabolically active, they can no longer produce daughter cells. This observation is central to the clonal exhaustion hypothesis, a mechanism cited to explain age-associated immune dysfunction. In this hypothesis, repeated division of lymphocytes leads to a replicative limit, after which they enter the senescent phase but are not lost from the pool of T cells. (...) Advancing age would then be associated with an increase in the number of T cells that are unable to proliferate to a stimulus which induces a proliferative response in T cells from younger individuals. This hypothesis seems both logical and reasonable and is supported by data from both humans and mice with the demonstration of an age-related accumulation of senescent T cells in both species. However, there is an apparent paradox. The paradox arises because the onset of immunosenescence appears to be more closely linked to the life span of the animal rather than the life span of the lymphocyte. BioEssays 21:519–524, 1999. © 1999 John Wiley & Sons, Inc. (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)

Protein‐carbohydrate interactions have been found to be important in many steps in lymphocyte recirculation and inflammatory responses. A family of carbohydrate‐binding proteins or lectins, termed selectins, has been discovered and shown to be involved directly in these processes. The three known selectins, termed L‐, E‐ and P‐selectins, have domains homologous to other Ca2+‐dependent (C‐type) lectins. L‐selectin is expressed constitutively on lymphocytes, E‐selectin is expressed by activated endothelial cells, and P‐selectin is expressed by activated platelets and endothelial cells. Here, we (...) review the nature of the carbohydrate determinants in tissues recognized by these selectins. The expression of specific sialylated, fucosylated and sulfated carbohydrates in activated endothelium and high endothelial venules promotes interactions with L‐selectin on leukocyte surfaces. In contrast, E‐ and P‐selectins recognize specific carbohydrate determinants related to sialyl Lex antigen on neutrophil and monocyte surfaces. The discovery of the selectins has generated excitemient among glycoconjugate researchers that other carbohydrate‐binding proteins and their cognate ligands will be found to function in regulating many types of cellular interactions. (shrink)

Indoleamine 2,3‐dioxygenase (IDO) is the rate‐limiting enzyme in conversion of tryptophan to kynurenines, feeding de novo nicotinamide synthesis. IDO orchestrates materno‐foetal tolerance, increasing human reproductive fitness. IDO mediates immune suppression through depletion of tryptophan required by T lymphocytes and other mechanisms. IDO is expressed by alternatively activated macrophages, suspected to play a key role in tuberculosis (TB) pathogenesis. Unlike its human host, Mycobacterium tuberculosis can synthesize tryptophan, suggesting possible benefit to the host from infection with the microbe. Intriguingly, nicotinamide analogues (...) are used to treat TB. In reviewing this field, it is postulated that flux through the nicotinamide synthesis pathway reflects switching between aerobic glycolysis and oxidative phosphorylation in M. tuberculosis‐infected macrophages. The evolutionary cause of such shifts may be ancient mitochondrial behavior related to reproductive fitness. Evolutionary perspectives on the IDO pathway may elucidate why, after centuries of co‐existence with the Tubercle bacillus, humans still remain susceptible to TB disease. (shrink)

Mouse pre‐implantation development appears to be under the control of paracrine and autocrine growth factors. The epithelium of the oviduct and the uterus together, with the population of macrophages and lymphocytes present in the reproductive tract from the onset of pregnancy, are thought to be the major sources of paracrine growth factors targeted to the developing embryos. Some of the growth factors are synthesized by both uterine epithelial cells and activated lympho‐hematopoietic cells, suggesting a partial overlap of the regulatory signals (...) used by the reproductive and lympho‐hematopoietic systems. Such growth factors may be the long sought‐after mediators of the synchrony between the pre‐implantation embryo and the sex‐steroid hormone‐induced changes in the uterus. (shrink)

Two types of interleukin 1 (IL‐1α and IL‐1β) have been defined by purifying the molecules from activated human peripheral blood cells, followed by cloning and expressing the molecules in Escherichia coli. Both types of IL‐1 stimulate proliferation and differentiation of T‐ and B‐lymphocytes and induce cartilage proteoglycan degradation but differ in other properties. For example, demineralization and appears to be a major mediator in the pathogenesis of joint erosion in rheumatoid arthritis. Synthetic adjuvants elicit the production of IL‐1 separate from (...) endogenous pyrogen, and this property is required for the new generation of vaccines based on antigens produced by recombinant DNA technology. (shrink)

The discovery of a stable latent reservoir for HIV‐1 in resting memory CD4+ T cells provides a mechanism for lifelong persistence of HIV‐1. The long‐lived latently infected cells persist in spite of prolonged highly active antiretroviral therapy and present a major barrier to a cure of HIV‐1 infection. In this review, we discuss the current understanding of HIV‐1 persistence and latent viral infection in the context of effective antiretroviral therapy and the recent progress in purging latent viral reservoirs. Recent studies (...) demonstrate that reactivation of latent HIV‐1 is a promising strategy for the depletion of these viral reservoirs. A thorough evaluation of the anti‐latency activity of drug candidates should include the measurement of changes in intracellular viral RNA, plasma virus levels, and the size of latent viral reservoirs, as well as potential adverse effects. Currently, there are several technical barriers to the evaluation of anti‐latency drugs in vivo. We also discuss these challenging issues that remain unresolved. (shrink)

Goal‐directed cognition is often discussed in terms of specialized memory structures like the “goal stack.” The goal‐activation model presented here analyzes goal‐directed cognition in terms of the general memory constructs of activation and associative priming. The model embodies three predictive constraints: (1) the interference level, which arises from residual memory for old goals; (1) the strengthening constraint, which makes predictions about time to encode a new goal; and (3) the priming constraint, which makes predictions about the role of (...) cues in retrieving pending goals. These constraints are formulated algebraically and tested through simulation of latency and error data from the Tower of Hanoi, a means‐ends puzzle that depends heavily on suspension and resumption of goals. Implications of the model for understanding intention superiority, postcompletion error, and effects of task interruption are discussed. (shrink)

Background: The broad autism phenotype includes subclinical autistic characteristics found to have a higher prevalence in unaffected family members of individuals with autism. These characteristics primarily affect the social aspects of language, communication, and human interaction. The current research focuses on possible neurobehavioral characteristics associated with the broad autism phenotype. Methods: We used a face-processing task associated with atypical patterns of gaze fixation and brain function in autism while collecting brain functional magnetic resonance imaging (fMRI) and eye tracking in unaffected (...) siblings of individuals with autism. Results: We found robust differences in gaze fixation and brain function in response to images of human faces in unaffected siblings compared with typically developing control individuals. The siblings’ gaze fixations and brain activation patterns during the face processing task were similar to that of the autism group and showed decreased gaze fixation along with diminished fusiform activation compared with the control group. Furthermore, amygdala volume in the siblings was similar to the autism group and was significantly reduced compared with the control group. Conclusions: Together, these findings provide compelling evidence for differences in social/emotional processing and underlying neural circuitry in siblings of individuals with autism, supporting the notion of unique endophenotypes associated with the broad autism phenotype. (shrink)

Time processing is a multifaceted skill crucial for managing different aspects of life. In the current work, we explored the relationship between interoception and time processing by examining research on clinical models. We investigated whether time processing deficits are associated with dysfunction of the interoceptive system and/or insular cortex activity, which is crucial in decoding internal body signaling. Furthermore, we explored whether insular activation predicts the subjective experience of time (that is, the subjective duration of a target stimulus to (...) be timed). Overall, our work suggests that alteration of the interoceptive system could be a common psychophysiological hallmark of mental disorders affected by time processing deficits. (shrink)