RESUMEN
Failures in peripheral immune tolerance mechanisms create a permissive environment for autoimmune diabetes initiation and disease progression. Biomarker analyses provide tools that allow recognition of this loss of tolerance, reflecting a serial acquisition of pathogenic characteristics causally linked to islet ß-cell dysfunction and death. Autoimmune effector cell activation and expansion, ineffective immune regulation, and tissue response to injury during active disease each represent challenges to homeostasis; however, they also represent targets for therapeutic intervention, with the potential for restoration of tolerance. Limited success in recent clinical trials demonstrates that tolerance in type 1 diabetes (T1D) is achievable, but currently occurs in few subjects and is not durable in most. Combining therapeutic agents to rebuild multiple immune components to restore tolerance, particularly addressing both effector and regulatory T-cell dysfunction, is needed.
Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 1/inmunología , Humanos , Linfocitos T Reguladores/inmunología , Células Secretoras de Insulina/inmunología , Tolerancia Inmunológica/inmunología , Tolerancia Periférica/inmunología , Animales , AutoinmunidadRESUMEN
Immunological tolerance is established and maintained by a diverse array of safeguards that work together to protect against autoimmunity. Despite the identification of numerous tolerogenic processes, the basis for cooperation among them remains poorly understood. We sought to identify synergy among several well-defined tolerance mediators that alone provide protection only from mild autoimmune symptoms in C57BL/6 mice: BIM, AIRE, CBL-B, and PD-1. Survey of a range of compound mutant mice revealed that the combined loss of the autoimmune regulator, AIRE, with PD-1 unleashed a spontaneous, lethal autoimmune disease. Pdcd1−/−Aire−/− mice succumbed to cachexia before adulthood, with near-complete destruction of the exocrine pancreas. Such fatal autoimmunity was not observed in Pdcd1−/−Bim−/−, Bim−/−Aire−/−, or Cblb−/−Bim−/− mice, suggesting that the cooperation between AIRE-mediated and PD-1mediated tolerance was particularly potent. Immune profiling revealed largely normal development of FOXP3+ regulatory T (Treg) cells in Pdcd1−/−Aire−/− mice, yet excessive, early activation of effector T cells. Adoptive transfer experiments demonstrated that autoimmune exocrine pancreatitis was driven by conventional CD4+ T cells and could not be prevented by the cotransfer of Treg cells from wild-type mice. The development of autoimmunity in mixed bone marrow chimeras supported these observations, indicating that failure of recessive tolerance was responsible for disease. These findings reveal a potent tolerogenic axis between AIRE and PD-1 that has implications for our understanding of how immune checkpoint blockade might synergize with subclinical defects in central tolerance to elicit autoimmune disease.
Asunto(s)
Pancreatitis Autoinmune , Tolerancia Inmunológica , Tolerancia Periférica , Receptor de Muerte Celular Programada 1 , Factores de Transcripción , Animales , Pancreatitis Autoinmune/genética , Pancreatitis Autoinmune/inmunología , Autoinmunidad/genética , Tolerancia Inmunológica/genética , Ratones , Ratones Endogámicos C57BL , Tolerancia Periférica/genética , Tolerancia Periférica/inmunología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/fisiología , Timo/inmunología , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Proteína AIRERESUMEN
T cell anergy is an important peripheral tolerance mechanism. We studied how T cell anergy is established using an anergy model in which the Zap70 hypermorphic mutant W131A is coexpressed with the OTII TCR transgene (W131AOTII). Anergy was established in the periphery, not in the thymus. Contrary to enriched tolerance gene signatures and impaired TCR signaling in mature peripheral CD4 T cells, CD4SP thymocytes exhibited normal TCR signaling in W131AOTII mice. Importantly, the maintenance of T cell anergy in W131AOTII mice required antigen presentation via MHC-II. We investigated the functional importance of the inhibitory receptor PD-1 and the E3 ubiquitin ligases Cbl-b and Grail in this model. Deletion of each did not affect expression of phenotypic markers of anergic T cells or T reg numbers. However, deletion of Cbl-b, but not Grail or PD-1, in W131AOTII mice restored T cell responsiveness and signaling. Thus, Cbl-b plays an essential role in the establishment and/or maintenance of unresponsiveness in T cell anergy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Linfocitos T CD4-Positivos/inmunología , Proteínas Proto-Oncogénicas c-cbl/inmunología , Linfocitos T Reguladores/inmunología , Animales , Anergia Clonal/inmunología , Tolerancia Inmunológica/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Transgénicos , Tolerancia Periférica/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal/inmunología , Ubiquitina-Proteína Ligasas/inmunología , Proteína Tirosina Quinasa ZAP-70/inmunologíaRESUMEN
Following their exit from the thymus, T cells are endowed with potent effector functions but must spare host tissue from harm. The fate of these cells is dictated by a series of checkpoints that regulate the quality and magnitude of T cell-mediated immunity, known as tolerance checkpoints. In this Perspective, we discuss the mediators and networks that control the six main peripheral tolerance checkpoints throughout the life of a T cell: quiescence, ignorance, anergy, exhaustion, senescence and death. At the naive T cell stage, two intrinsic checkpoints that actively maintain tolerance are quiescence and ignorance. In the presence of co-stimulation-deficient T cell activation, anergy is a dominant hallmark that mandates T cell unresponsiveness. When T cells are successfully stimulated and reach the effector stage, exhaustion and senescence can limit excessive inflammation and prevent immunopathology. At every stage of the T cell's journey, cell death exists as a checkpoint to limit clonal expansion and to terminate unrestrained responses. Here, we compare and contrast the T cell tolerance checkpoints and discuss their specific roles, with the aim of providing an integrated view of T cell peripheral tolerance and fate regulation.
Asunto(s)
Apoptosis/inmunología , Senescencia Celular/inmunología , Anergia Clonal/inmunología , Memoria Inmunológica/inmunología , Tolerancia Periférica/inmunología , Linfocitos T/inmunología , Muerte Celular/inmunología , HumanosRESUMEN
BACKGROUND: In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA. METHOD: Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation (n = 15). RESULTS: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients. CONCLUSION: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.
Asunto(s)
Artritis Reumatoide/inmunología , Ganglios Linfáticos/inmunología , Tolerancia Periférica/inmunología , Células del Estroma/inmunología , Adulto , Animales , Anticuerpos Antiproteína Citrulinada/inmunología , Anticuerpos Antiproteína Citrulinada/metabolismo , Artritis Reumatoide/patología , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Células Cultivadas , Femenino , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Humanos , Ganglios Linfáticos/citología , Masculino , Ratones , Persona de Mediana Edad , Células del Estroma/citología , Células del Estroma/metabolismoRESUMEN
A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached; however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically relevant B cell responses without the use of an engineered BCR. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. In this study, we use a strong adjuvant to provide bystander innate and adaptive signals that promote B cell responsiveness in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although self-reactive B cells are recruited into the germinal center, their development does not proceed, possibly because of rapid counterselection. Consequently, differentiation of plasma cells is blunted, and Ab responses are transient and devoid of affinity maturation. We propose this approach, and these tools can be more widely applied to track Ag-specific B cell responses to more disease-relevant Ags, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.
Asunto(s)
Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Tolerancia Inmunológica/inmunología , Tolerancia Periférica/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Animales , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Autoinmunidad/inmunología , Diferenciación Celular/inmunología , Femenino , Centro Germinal/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Plasmáticas/inmunologíaRESUMEN
Treg cells are the immune system's in-house combatants against pathological immune activation. Because they are vital to maintenance of peripheral tolerance, it is important to understand how they perform their functions. To this end, various mechanisms have been proposed for Treg-mediated immune inhibition. A major group of mechanisms picture Treg cells as skilled thieves stealing a plethora of molecules that would otherwise promote immune effector functions. This suggests that several million years of evolution have endowed Treg cells with efficient ways to deprive immune effectors of activating stimuli to prevent immunopathology for survival of the host. Although we are still long way from deciphering their complete set of tricks, this review will focus on the types of "crimes" committed by these master thieves in both secondary lymphoid organs and non-lymphoid tissue.
Asunto(s)
Inmunidad/inmunología , Linfocitos T Reguladores/inmunología , Animales , Citocinas/inmunología , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica/inmunología , Tolerancia Periférica/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/fisiologíaRESUMEN
Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.
Asunto(s)
Antígenos B7/fisiología , Proteínas de la Membrana/fisiología , Tolerancia Periférica/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales , Antígenos B7/genética , Activación de Linfocitos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tolerancia Periférica/genética , Receptores de Antígenos de Linfocitos T/fisiologíaRESUMEN
Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.
Asunto(s)
Autoinmunidad/inmunología , Tolerancia Periférica/inmunología , Timo/inmunología , Factores de Transcripción/inmunología , Animales , Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Modelos Animales de Enfermedad , Humanos , Islotes Pancreáticos/inmunología , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Linfocitos T/inmunología , Factores de Transcripción/genética , Proteína AIRERESUMEN
Although central tolerance mechanisms purge self-reactive B cells during development based on BCR signal strength, mechanisms that block the differentiation of autoreactive effector and memory B cells from mature pools remain poorly understood. Prior observations implicate nucleic acid sensing TLRs in autoimmunity, and more recent findings show that TLR9 is also involved in maintaining peripheral tolerance. Studies of the immunological changes that occur during aging revealed a subset of B cells denoted Age-associated B cells which expands in settings of aging and in autoimmunity. Further studies demonstrated that TLR9 signals poise activated B cells to adopt an Age-associated B cell phenotype, but BCR-delivered TLR9 signals cause programmed cell death that, if circumvented by costimulation, allows continued differentiation to the ABC fate. Together, these observations suggest molecular pattern recognition, rather than BCR epitope specificity per se, is a fundamental mediator of tolerogenic outcomes in the peripheral B cell activation.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Tolerancia Periférica/inmunología , Factores de Edad , Animales , Autoinmunidad , Epítopos de Linfocito B/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Humoral , Inmunidad Innata , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Receptor Toll-Like 9/metabolismoRESUMEN
There is a growing appreciation that the extracellular matrix (ECM) contributes to both the maintenance of immune tolerance in healthy tissues and to its loss at sites of autoimmunity. Here, we review recent literature on the role of ECM and particularly the glycosaminoglycans hyaluronan and heparan sulfate in the development of autoimmune, type 1 diabetes (T1D). Data from transplant models suggest that healthy islets are embedded within an intact ECM that supports beta-cell homeostasis and provides physical and immunoregulatory barriers against immune infiltration. However, studies of human insulitis as well as the non-obese diabetic (NOD) and DORmO mouse models of T1D indicate that autoimmune insulitis is associated with the degradation of basement membrane structures, the catabolism of the islet interstitium, and the accumulation of a hyaluronan-rich, pro-inflammatory ECM. Moreover, in these models of autoimmune diabetes, either the pharmacologic inhibition of heparan sulfate catabolism, the reduction of hyaluronan synthesis, or the targeting of the pathways that sense these ECM changes can all prevent beta-cell destruction. Together these data support an emerging paradigm that in healthy islets the local ECM contributes to both immune tolerance and beta-cell homeostasis while in chronic inflammation the islet ECM is permissive to immune infiltration and beta-cell destruction. Therapies that support ECM-mediated 'barrier tolerance' may have potential as adjunctive agents in combination regimens designed to prevent or treat autoimmunity.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Matriz Extracelular/inmunología , Tolerancia Periférica/inmunología , Animales , Humanos , Islotes Pancreáticos/inmunologíaRESUMEN
Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of α and ß subunits that mediate cell-to-cell and cell-to-extracellular matrix interactions, play an important role in facilitating Treg cell contact-mediated suppression. In this article, we show that integrin activation plays an essential, previously unappreciated role in maintaining murine Treg cell function. Treg cell-specific loss of talin, a ß integrin-binding protein, or expression of talin(L325R), a mutant that selectively abrogates integrin activation, resulted in lethal systemic autoimmunity. This dysfunction could be attributed, in part, to a global dysregulation of the Treg cell transcriptome. Activation of integrin α4ß1 led to increased suppressive capacity of the Treg cell pool, suggesting that modulating integrin activation on Treg cells may be a useful therapeutic strategy for autoimmune and inflammatory disorders. Taken together, these results reveal a critical role for integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell function.
Asunto(s)
Integrinas/inmunología , Tolerancia Periférica/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/inmunología , Inflamación/inmunología , Ratones , Talina/inmunología , Transcriptoma/inmunologíaRESUMEN
Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-ß and Foxp3-expressing Treg cells. However, whether TGF-ß and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-ß receptor II (TßRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-ß promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Tolerancia Periférica/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Inmunidad Adaptativa/inmunología , Animales , Autoinmunidad/inmunología , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inmunidad Innata/inmunología , Inflamación/metabolismo , Ratones , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
A subset of characterized HIV-1 broadly neutralizing antibodies (bnAbs) are polyreactive with additional specificities for self-antigens and it has been proposed immunological tolerance may present a barrier to their participation in protective humoral immunity. We address this hypothesis by immunizing autoimmune-prone mice with HIV-1 Envelope (Env) and characterizing the primary antibody response for HIV-1 neutralization. We find autoimmune mice generate neutralizing antibody responses to tier 2 HIV-1 strains with alum treatment alone in the absence of Env. Importantly, experimentally breaching immunological tolerance in wild-type mice also leads to the production of tier 2 HIV-1-neutralizing antibodies, which increase in breadth and potency following Env immunization. In both genetically prone and experimentally induced mouse models of autoimmunity, increased serum levels of IgM anti-histone H2A autoantibodies significantly correlated with tier 2 HIV-1 neutralization, and anti-H2A antibody clones were found to neutralize HIV-1. These data demonstrate that breaching peripheral tolerance permits a cross-reactive HIV-1 autoantibody response able to neutralize HIV-1.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Tolerancia Periférica/inmunología , Animales , Formación de Anticuerpos/inmunología , Autoanticuerpos/inmunología , Reacciones Cruzadas/inmunología , Femenino , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Inmunoglobulina M/inmunología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Efforts to understand autoimmunity have been pursued relentlessly for several decades. It has become apparent that the immune system evolved multiple mechanisms for controlling self-reactivity, and defects in one or more of these mechanisms can lead to a breakdown of tolerance. Among the multitude of lesions associated with disease, the most common seem to affect peripheral tolerance rather than central tolerance. The initial trigger for both systemic autoimmune disorders and organ-specific autoimmune disorders probably involves the recognition of self or foreign molecules, especially nucleic acids, by innate sensors. Such recognition, in turn, triggers inflammatory responses and the engagement of previously quiescent autoreactive T cells and B cells. Here we summarize the most prominent autoimmune pathways and identify key issues that require resolution for full understanding of pathogenic autoimmunity.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Linfocitos B/inmunología , Autotolerancia/inmunología , Linfocitos T/inmunología , Animales , Tolerancia Central/inmunología , Humanos , Tolerancia Periférica/inmunologíaRESUMEN
Reestablishment of immune tolerance to the insulin-producing beta cells is the desired goal for type 1 diabetes (T1D) treatment and prevention. Immune tolerance to multiple islet antigens is defective in individuals with T1D, but the mechanisms involved are multifaceted and may involve loss of thymic and peripheral tolerance. In this review we discuss our current understanding of the varied mechanisms by which peripheral tolerance to islet antigens is maintained in healthy individuals where genetic protection from T1D is present and how this fails in those with genetic susceptibility to disease. Novel findings in regards to expression of neo-islet antigens, non-classical regulatory cell subsets and the impact of specific genetic variants on tolerance induction are discussed.
Asunto(s)
Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Células Secretoras de Insulina/inmunología , Tolerancia Periférica/inmunología , Animales , Tolerancia Central/inmunología , Humanos , Modelos Inmunológicos , Linfocitos T Reguladores/inmunología , Timo/inmunologíaRESUMEN
Therapeutic cancer vaccines aim to induce durable antitumor immunity that is capable of systemic protection against tumor recurrence or metastatic disease. Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, an ex vivo dendritic cell vaccine for prostate cancer, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines. The clinical success of checkpoint blockade has underscored the role of peripheral tolerance mechanisms in limiting vaccine responses and highlighted the potential for combination therapies. Recent advances in transcriptome sequencing, computational modeling, and material engineering further suggest new opportunities to intensify cancer vaccines. This review will discuss the major approaches to therapeutic cancer vaccination and explore recent advances that inform the design of the next generation of cancer vaccines.
Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Inmunoterapia Activa/tendencias , Neoplasias/terapia , Animales , Antígenos de Neoplasias/genética , Apoptosis/inmunología , Ingeniería Biomédica/métodos , Vacunas contra el Cáncer/inmunología , Humanos , Ratones , Neoplasias/inmunología , Virus Oncolíticos/inmunología , Tolerancia Periférica/inmunologíaRESUMEN
Immune responses to protein antigens involve CD4(+) and CD8(+) T cells, which follow distinct programs of differentiation. Naïve CD8 T cells rapidly develop cytotoxic T-cell (CTL) activity after T-cell receptor stimulation, and we have previously shown that this is accompanied by suppressive activity in the presence of specific cytokines, i.e. IL-12 and IL-4. Cytokine-induced CD8(+) regulatory T (Treg) cells are one of several Treg-cell phenotypes and are Foxp3(-) IL-10(+) with contact-dependent suppressive capacity. Here, we show they also express high level CD39, an ecto-nucleotidase that degrades extracellular ATP, and this contributes to their suppressive activity. CD39 expression was found to be upregulated on CD8(+) T cells during peripheral tolerance induction in vivo, accompanied by release of IL-12 and IL-10. CD39 was also upregulated during respiratory tolerance induction to inhaled allergen and on tumor-infiltrating CD8(+) T cells. Production of IL-10 and expression of CD39 by CD8(+) T cells was independently regulated, being respectively blocked by extracellular ATP and enhanced by an A2A adenosine receptor agonist. Our results suggest that any CTL can develop suppressive activity when exposed to specific cytokines in the absence of alarmins. Thus negative feedback controls CTL expansion under regulation from both nucleotide and cytokine environment within tissues.
Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Tolerancia Inmunológica , Interleucina-12/metabolismo , Interleucina-4/metabolismo , Tolerancia Periférica/inmunología , Adenosina Trifosfato/metabolismo , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Femenino , Interleucina-12/farmacología , Interleucina-4/farmacología , Activación de Linfocitos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Melanoma Experimental , Ratones , Ratones Noqueados , Receptores Purinérgicos P1/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismoRESUMEN
The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.
Asunto(s)
Autoinmunidad/inmunología , Diferenciación Celular/inmunología , Anergia Clonal/inmunología , Histocompatibilidad Materno-Fetal/inmunología , Tolerancia Periférica/inmunología , Células Precursoras de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Artritis Experimental/inmunología , Linfocitos T CD4-Positivos/inmunología , Proliferación Celular , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T , Immunoblotting , Masculino , Ratones , Ratones Noqueados , Neuropilina-1/metabolismo , Embarazo , Receptores de Antígenos de Linfocitos T/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Autotolerancia , Timocitos/inmunologíaRESUMEN
Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines affect the immune system in a context-dependent manner. Here we show that nonspecific bystander inflammation conditions naive CD4(+) T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This results in inhibition of immune responses in vivo via a Foxp3-dependent effect on antigen-specific naive CD4(+) T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self-antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the idea that early tuning of the immune system by infection affects the long-term quality of immune regulation.