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BACKGROUND: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. METHODS: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. RESULTS: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. CONCLUSIONS: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.
Some proteins, such as programmed cell death protein 1 (PD1), can stop the immune system from attacking cancer cells, allowing cancers to grow. Therapies targeting these proteins can be highly effective, but tumors can become resistant. It is important to identify factors involved in this resistance to develop improved cancer therapies. Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a protein that inhibits an immune response and its levels have been associated with poor patient outcomes. We applied a method that allows for the detection of proteins on a single cell to uncover CEACAM1 patterns in melanoma. We found that increased CEACAM1 expression levels on multiple different immune cell types was associated with tumors that were resistant to therapy. These findings may help us to understand the role of CEACAM1 in cancer and to develop better cancer therapies.
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The human (h) CEACAM1 GFCC' face serves as a binding site for homophilic and heterophilic interactions with various microbial and host ligands. hCEACAM1 has also been observed to form oligomers and micro-clusters on the cell surface which are thought to regulate hCEACAM1-mediated signaling. However, the structural basis for hCEACAM1 higher-order oligomerization is currently unknown. To understand this, we report a hCEACAM1 IgV oligomer crystal structure which shows how GFCC' face-mediated homodimerization enables highly flexible ABED face interactions to arise. Structural modeling and nuclear magnetic resonance (NMR) studies predict that such oligomerization is not impeded by the presence of carbohydrate side-chain modifications. In addition, using UV spectroscopy and NMR studies, we show that oligomerization is further facilitated by the presence of a conserved metal ion (Zn++ or Ni++) binding site on the G strand of the FG loop. Together these studies provide biophysical insights on how GFCC' and ABED face interactions together with metal ion binding may facilitate hCEACAM1 oligomerization beyond dimerization.
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Antígenos CD , Moléculas de Adhesión Celular , Antígenos CD/metabolismo , Sitios de Unión , Carbohidratos , Moléculas de Adhesión Celular/metabolismo , HumanosRESUMEN
Human (h) carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) function depends upon IgV-mediated homodimerization or heterodimerization with host ligands, including hCEACAM5, hTIM-3, PD-1, and a variety of microbial pathogens. However, there is little structural information available on how hCEACAM1 transitions between monomeric and dimeric states which in the latter case is critical for initiating hCEACAM1 activities. We therefore mutated residues within the hCEACAM1 IgV GFCC' face including V39, I91, N97, and E99 and examined hCEACAM1 IgV monomer-homodimer exchange using differential scanning fluorimetry, multi-angle light scattering, X-ray crystallography and/or nuclear magnetic resonance. From these studies, we describe hCEACAM1 homodimeric, monomeric and transition states at atomic resolution and its conformational behavior in solution through NMR assignment of the wildtype (WT) hCEACAM1 IgV dimer and N97A mutant monomer. These studies reveal the flexibility of the GFCC' face and its important role in governing the formation of hCEACAM1 dimers and selective heterodimers.
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Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Antígenos CD/química , Antígenos CD/genética , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/genética , Cristalografía por Rayos X , Dispersión Dinámica de Luz , Fluorometría , Humanos , Espectroscopía de Resonancia Magnética , Mutación , Conformación Proteica , Multimerización de Proteína , Relación Estructura-ActividadRESUMEN
Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma.
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Antígenos CD/metabolismo , Antígeno Carcinoembrionario/metabolismo , Moléculas de Adhesión Celular/metabolismo , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Neutrófilos/inmunología , Células A549 , Animales , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Células HT29 , Humanos , Ratones , Neutrófilos/patologíaRESUMEN
The type I membrane protein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) distinctively exhibits significant alternative splicing that allows for tunable functions upon homophilic binding. CEACAM1 is highly expressed in the tumor environment and is strictly regulated on lymphocytes such that its expression is restricted to activated cells where it is now recognized to function in tolerance pathways. CEACAM1 is also an important target for microbes which have co-opted these attributes of CEACAM1 for the purposes of invading the host and evading the immune system. These properties, among others, have focused attention on CEACAM1 as a unique target for immunotherapy in autoimmunity and cancer. This review examines recent structural information derived from the characterization of CEACAM1:CEACAM1 interactions and heterophilic modes of binding especially to microbes and how this relates to CEACAM1 function. Through this, we aim to provide insights into targeting CEACAM1 for therapeutic intervention.
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Antígenos CD/inmunología , Moléculas de Adhesión Celular/inmunología , Animales , Antígenos CD/química , Moléculas de Adhesión Celular/antagonistas & inhibidores , Moléculas de Adhesión Celular/química , HumanosRESUMEN
INTRODUCTION: To study the factors affecting the intent to leave of healthcare workers who serve in underserviced areas of Taiwan, the authors tested the mediating role of both professional and organizational commitment in the relationship between perceived investment of employee development and intention to leave among these healthcare workers. METHOD: This study was designed as a cross-sectional study using a well-organized questionnaire with major study variables consisting of perceived investment in employees' development (PIED), Meyer's occupational and organizational normative commitment, and intent to leave. In total, 692 healthcare workers from 48 health centers were enrolled for study; 616 people, including 415 (68.9%) from mountainous areas and 187 (31.1%) from isolated islands, responded and were valid for analysis. The response rate was 87%. RESULTS: The healthcare worker's PIED was positively correlated with both professional normative commitment and organizational normative commitment and negatively correlated with an individual's intent to leave. The dual normative commitments mediate completely the relationship between PIED and intention to leave in those health workers with government subsidy, while no such effect was noted in those without. CONCLUSION: The employee's dual commitments of professional and organizational normative commitment mediated the relationship between perceived investment of employee development and intention to leave. The government's investment in on-the-job training and career planning for the healthcare workers in both remote areas and isolated islands is important to enforce their professional and organizational normative commitment, and to retain the workforce in these underserviced areas.
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Administración de Personal/normas , Reorganización del Personal/estadística & datos numéricos , Personal de Hospital/normas , Desarrollo de Personal/organización & administración , Adulto , Estudios Transversales , Femenino , Humanos , Satisfacción en el Trabajo , Masculino , Cultura Organizacional , TaiwánRESUMEN
T-cell immunoglobulin and mucin domain containing protein-3 (TIM-3) is an important immune regulator. Here, we describe a novel high resolution (1.7 Å) crystal structure of the human (h)TIM-3 N-terminal variable immunoglobulin (IgV) domain with bound calcium (Ca++) that was confirmed by nuclear magnetic resonance (NMR) spectroscopy. Significant conformational differences were observed in the B-C, C'-Câ³ and C'-D loops of hTIM-3 compared to mouse (m)TIM-3, hTIM-1 and hTIM-4. Further, the conformation of the C-C' loop of hTIM-3 was notably different from hTIM-4. Consistent with the known metal ion-dependent binding of phosphatidylserine (PtdSer) to mTIM-3 and mTIM-4, the NMR spectral analysis and crystal structure of Ca++-bound hTIM-3 revealed that residues in the hTIM-3 F-G loop coordinate binding to Ca++. In addition, we established a novel biochemical assay to define hTIM-3 functionality as determined by binding to human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). These studies provide new insights useful for understanding and targeting hTIM-3.
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Cristalografía por Rayos X/métodos , Receptor 2 Celular del Virus de la Hepatitis A/química , Resonancia Magnética Nuclear Biomolecular/métodos , Linfocitos T/metabolismo , Secuencia de Aminoácidos , Animales , Humanos , Ratones , Conformación Proteica , Homología de Secuencia de AminoácidoRESUMEN
Natural-killer group 2 member D (NKG2D) is a well-characterized activating receptor expressed by natural killer (NK) cells, NKT cells, activated CD8+ T cells, subsets of γδ+ T cells, and innate-like T cells. NKG2D recognizes multiple ligands (NKG2D-ligands) to mount an innate immune response against stressed, transformed, or infected cells. NKG2D-ligand surface expression is tightly restricted on healthy cells through transcriptional and post-transcriptional mechanisms, while transformed or infected cells express the ligands as a danger signal. Recent studies have revealed that unfolded protein response pathways during endoplasmic reticulum (ER) stress result in upregulation of ULBP-related protein via the protein kinase RNA-like ER kinase-activating factor 4-C/EBP homologous protein (PERK-ATF4-CHOP) pathway, which can be linked to the pathogenesis of autoimmune diseases. Transformed cells, however, possess mechanisms to escape NKG2D-mediated immune surveillance, such as upregulation of carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1), a negative regulator of NKG2D-ligands. In this review, we discuss mechanisms of NKG2D-ligand regulation, with a focus on newly discovered mechanisms that promote NKG2D-ligand expression on epithelial cells, including ER stress, and mechanisms that suppress NKG2D-ligand-mediated killing of cancer cells, namely by co-expression of CEACAM1.
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Both in vivo data in preclinical cancer models and in vitro data with T cells from patients with advanced cancer support a role for Tim-3 blockade in promoting effective anti-tumor immunity. Consequently, there is considerable interest in the clinical development of antibody-based therapeutics that target Tim-3 for cancer immunotherapy. A challenge to this clinical development is the fact that several ligands for Tim-3 have been identified: galectin-9, phosphatidylserine, HMGB1, and most recently, CEACAM1. These observations raise the important question of which of these multiple receptor:ligand relationships must be blocked by an anti-Tim-3 antibody in order to achieve therapeutic efficacy. Here, we have examined the properties of anti-murine and anti-human Tim-3 antibodies that have shown functional efficacy and find that all antibodies bind to Tim-3 in a manner that interferes with Tim-3 binding to both phosphatidylserine and CEACAM1. Our data have implications for the understanding of Tim-3 biology and for the screening of anti-Tim-3 antibody candidates that will have functional properties in vivo.
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CEACAM1 is an extensively studied cell surface molecule with established functions in multiple cancer types, as well as in various compartments of the immune system. Due to its multi-faceted role as a recently appreciated immune checkpoint inhibitor and tumor marker, CEACAM1 is an attractive target for cancer immunotherapy. Herein, we highlight CEACAM1's function in various immune compartments and cancer types, including in the context of metastatic disease. This review outlines CEACAM1's role as a therapeutic target for cancer treatment in light of these properties.
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T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.
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Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Tolerancia Inmunológica/inmunología , Proteínas de la Membrana/metabolismo , Receptores Virales/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Antígenos CD/química , Antígenos CD/inmunología , Autoinmunidad/inmunología , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/inmunología , Línea Celular , Neoplasias Colorrectales/inmunología , Modelos Animales de Enfermedad , Femenino , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Inflamación/inmunología , Inflamación/patología , Ligandos , Masculino , Proteínas de la Membrana/química , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Moleculares , Membrana Mucosa/inmunología , Membrana Mucosa/patología , Conformación Proteica , Multimerización de Proteína , Receptores Virales/química , Receptores Virales/inmunologíaRESUMEN
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on activated natural killer (NK) cells wherein it inhibits lysis of CEACAM1-bearing tumor cell lines. The mechanism for this is unknown. Here, we show that interleukin-2-induced expression of CEACAM1 on both mouse and primary human NK cells impairs the ability of NK gene complex group 2 member D (NKG2D) to stimulate cytolysis of CEACAM1-bearing cells. This process requires the expression of CEACAM1 on the NK cells and on the tumor cells, which is consistent with the involvement of trans-homophilic interactions between CEACAM1. Mechanistically, co-engagement of NKG2D and CEACAM1 results in a biochemical association between these two surface receptors and the recruitment of Src homology phosphatase 1 by CEACAM1 that leads to dephosphorylation of the guanine nucleotide exchange factor Vav1 and blockade of downstream signaling that is associated with the initiation of cytolysis. Thus, CEACAM1 on activated NK cells functions as an inhibitory receptor for NKG2D-mediated cytolysis, which has important implications for understanding the means by which CEACAM1 expression adversely affects tumor immunity.
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Antígeno Carcinoembrionario/metabolismo , Células Asesinas Naturales/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Animales , Apoptosis/inmunología , Antígeno Carcinoembrionario/genética , Línea Celular Tumoral , Humanos , Interleucina-2/metabolismo , Células Asesinas Naturales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogénicas c-vav/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Transducción de SeñalRESUMEN
Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues, which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with the generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens.
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Antígeno Carcinoembrionario/inmunología , Inmunidad Mucosa/inmunología , Intestinos/inmunología , Linfocitos T/inmunología , Secuencias de Aminoácidos/genética , Secuencias de Aminoácidos/inmunología , Animales , Antígeno Carcinoembrionario/genética , Antígeno Carcinoembrionario/metabolismo , Citoplasma/genética , Citoplasma/inmunología , Citoplasma/metabolismo , Homeostasis , Inmunidad Mucosa/genética , Inmunoglobulina A/genética , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Mucosa Intestinal/metabolismo , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Activación de Linfocitos , Metagenoma/inmunología , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Isoformas de Proteínas , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Linfocitos T/metabolismo , Tirosina/genética , Tirosina/inmunología , Tirosina/metabolismoRESUMEN
Although carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1) has been viewed as a tumor suppressor, increasing clinical evidence shows that high levels of CEACAM1 expression on tumors correlates with poor prognosis and high risk of metastasis. Here, we examined the consequences of CEACAM1 expression on tumor cells. We show that tumor cell-associated CEACAM1 causes intracellular retention of various NKG2D ligands in mouse and human tumor cells. CEACAM1-silenced tumor cells expressed more cell surface NKG2D ligands and exhibited greater sensitivity to natural killer cell-mediated cytolysis in vitro and rejection in vivo. Our studies reveal a novel mechanism through which CEACAM1-bearing tumor cells may escape immune-surveillance.
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Antígenos CD/inmunología , Antígeno Carcinoembrionario/inmunología , Moléculas de Adhesión Celular/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/agonistas , Neoplasias/inmunología , Escape del Tumor/inmunología , Animales , Antígenos CD/genética , Antígeno Carcinoembrionario/genética , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Humanos , Inmunidad Celular , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Ligandos , Ratones , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Metástasis de la Neoplasia , Neoplasias/patologíaRESUMEN
The central nervous system (CNS) is considered an immune-privileged organ that maintains an adaptable immune surveillance system. Dysregulated immune function within the CNS contributes to the development of brain tumor growth, and robust immune activation results in excessive inflammation. Human lymphocyte antigen-G (HLA-G) proteins with tolerogenic immunoreactivity have been implicated in various pathophysiological processes including immune surveillance, governing homeostasis and immune regulation. In this review, we describe the wealth of evidence for the involvement of HLA-G in the CNS under physiological and pathological conditions. Further, we review regulatory functions that may be applicable as beneficial strategies in the therapeutic manipulation of immune-mediated CNS immune responses. Additionally, we try to understand how this molecule cooperates with other CNS-resident cells to maintain normal immune homeostasis, while still facilitating the development of the appropriate immune responses.
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Sistema Nervioso Central/inmunología , Antígenos HLA/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Animales , Sistema Nervioso Central/patología , Antígenos HLA-G , Humanos , Tolerancia InmunológicaRESUMEN
This study attempted to investigate the role of emotional exhaustion as a mediator on the relationship between job demands-control (JDC) model and mental health. Three-wave data from 297 employees were collected. The results showed that job demands were positively related to emotional exhaustion, and increasing job demands will increase the level of emotional exhaustion. Job control was negatively associated with emotional exhaustion; therefore, increasing job control will decrease the level of emotional exhaustion. Emotional exhaustion was negatively related to mental health. Emotional exhaustion fully mediated the relationship between job demands and mental health, and partially mediated the positive relationship between job control and mental health. In addition, job control was positively associated with mental health directly. The remarkable finding of the present study was that emotional exhaustion served as the key mediator between the JDC model and mental health. Theoretical and managerial implications and limitations were discussed.
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Agotamiento Profesional/psicología , Emociones , Empleo/psicología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos PsicológicosRESUMEN
OBJECTIVE: We have recently described a novel population of natural regulatory T cells (T(reg)) that are characterized by the expression of HLA-G and may be found at sites of tissue inflammation (HLA-G(pos) T(reg)). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS). METHODS: Sixty-four patients with different types of MS, 9 patients with other neurological diseases, and 20 healthy donors were included in this study. Inflamed brain lesions from 5 additional untreated MS patients were examined. HLA-G(pos) T(reg) were analyzed in the cerebrospinal fluid (CSF) by flow cytometry and in inflammatory demyelinating lesions of MS brain specimens by immunohistochemistry. Functional capacity was accessed and transmigration was determined using an in vitro model of the human blood-brain barrier (BBB). RESULTS: HLA-G(pos) T(reg) were found enriched in the inflamed CSF of MS patients and in inflammatory demyelinating lesions of MS brain specimens. HLA-G(pos) T(reg) showed a strong propensity to transmigrate across BBB, which was vigorously driven by inflammatory chemokines, and associated with a gain of suppressive capacity upon transmigration. CSF-derived HLA-G(pos) T(reg) of MS patients represented a population of activated central memory activated T cells with an upregulated expression of inflammatory chemokine receptors and exhibiting full suppressive capacity. Unlike natural FoxP3-expressing T(reg), HLA-G(pos) T(reg) derived from peripheral blood were functionally unimpaired in MS. INTERPRETATION: In MS, HLA-G(pos) T(reg) may serve to control potentially destructive immune responses directly at the sites of CNS inflammation and to counterbalance inflammation once specifically recruited to the CNS.