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1.
J Autoimmun ; 79: 39-52, 2017 May.
Article in English | MEDLINE | ID: mdl-28126203

ABSTRACT

Regulatory T cells (Tregs) are a subset of CD4+ T cells with suppressive function and are critical for limiting inappropriate activation of T cells. Hence, the expansion of Tregs is an attractive strategy for the treatment of autoimmune diseases. Here, we demonstrate that the skin possesses the remarkable capacity to systemically expand Treg numbers by producing thymic stromal lymphopoietin (TSLP) in response to vitamin D receptor stimulation. An ∼2-fold increase in the proportion and absolute number of Tregs was observed in mice treated topically but not systemically with the Vitamin D3 analog MC903. This expansion of Tregs was dependent on TSLP receptor signaling but not on VDR signaling in hematopoietic cells. However, TSLP receptor expression by Tregs was not required for their proliferation. Rather, skin-derived TSLP promoted Treg expansion through dendritic cells. Importantly, treatment of skin with MC903 significantly lowered the incidence of autoimmune diabetes in non-obese diabetic mice and attenuated disease score in experimental autoimmune encephalomyelitis. Together, these data demonstrate that the skin has the remarkable potential to control systemic immune responses and that Vitamin D-mediated stimulation of skin could serve as a novel strategy to therapeutically modulate the systemic immune system for the treatment of autoimmunity.


Subject(s)
Cytokines/metabolism , Skin/immunology , Skin/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Animals , Biomarkers , Cholecalciferol/analogs & derivatives , Cholecalciferol/pharmacology , Cytokines/pharmacology , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocyte Count , Mice , Mice, Knockout , Mice, Transgenic , Models, Biological , Signal Transduction/drug effects , T-Lymphocytes, Regulatory/drug effects , Thymic Stromal Lymphopoietin
2.
Immun Inflamm Dis ; 4(2): 148-154, 2016 06.
Article in English | MEDLINE | ID: mdl-27891224

ABSTRACT

To maintain immune tolerance, regulatory T cell (Treg) numbers must be closely indexed to the number of conventional T cells (Tconvs) so that an adequate Treg:Tconv ratio can be maintained. Two factors important in this process are the cytokine interleukin-2 (IL-2) and T cell receptor (TCR) stimulation by major histocompatibility complex class II (MHC-II). Here, we report that in addition to TCR stimulation of Tregs themselves, the maintenance of Tregs also requires TCR signaling by Tconvs. We found that Tconvs produce IL-2 in response to self-peptide-MHC-II complexes and that Tconvs possessing more highly self-reactive TCRs express more IL-2 at baseline. Furthermore, selective disruption of TCR signaling in Tconvs led to a trend toward decreased expression of IL-2 and attenuated their ability to maintain Treg numbers. These data suggest that in order to maintain an adequate Treg:Tconv ratio, Tregs are continuously indexed to self-peptide-MHC-II-induced TCR signaling of Tconvs. These results have implications in attempts to modulate immune tolerance, as Treg numbers adjust to the self-reactivity, and ultimately IL-2 production by the T cells around them.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Immune Tolerance , T-Lymphocytes, Regulatory/immunology , Animals , Forkhead Transcription Factors , Interleukin-2 , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, T-Cell
5.
Blood ; 125(23): 3655-63, 2015 Jun 04.
Article in English | MEDLINE | ID: mdl-25788701

ABSTRACT

In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft-versus-host disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8(+) T cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8(+) T cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCT-recipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8(+) T cells to regain their GVT function. Indeed, short-term treatment with anti-NKG2D antibody restored GVT effects while maintaining an attenuated GVHD state. NKG2D expression was also detected on CD8(+) T cells from allogeneic HSCT patients and trended to be higher in those with active GVHD. Together, these data support a novel role for NKG2D expression by CD8(+) T cells during allogeneic HSCT, which could be potentially therapeutically exploited to separate GVHD from GVT effects.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Gene Expression Regulation/immunology , Graft vs Host Disease/immunology , Graft vs Tumor Effect/immunology , Hematopoietic Stem Cell Transplantation , NK Cell Lectin-Like Receptor Subfamily K/immunology , Allografts , Animals , Antibodies, Neutralizing/pharmacology , CD8-Positive T-Lymphocytes/pathology , Disease Models, Animal , Graft vs Host Disease/genetics , Graft vs Host Disease/pathology , Graft vs Tumor Effect/drug effects , Graft vs Tumor Effect/genetics , Mice , Mice, Knockout , NK Cell Lectin-Like Receptor Subfamily K/antagonists & inhibitors , NK Cell Lectin-Like Receptor Subfamily K/genetics
6.
Eur J Immunol ; 44(9): 2712-20, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24894919

ABSTRACT

Natural Treg cells acquire their lineage-determining transcription factor Foxp3 during development in the thymus and are important in maintaining immunologic tolerance. Here, we analyzed the composition of the thymic Treg-cell pool using RAG2-GFP/FoxP3-RFP dual reporter mice and found that a population of long-lived GFP(-) Treg cells exists in the thymus. These long-lived Treg cells substantially increased with age, to a point where they represent >90% of the total thymic Treg-cell pool at 6 months of age. In contrast, long-lived conventional T cells remained at ∼ 15% of the total thymic pool at 6 months of age. Consistent with these studies, we noticed that host-derived Treg cells represented a large fraction (∼ 10%) of the total thymic Treg-cell pool in bone marrow chimeras, suggesting that long-lived Treg cells also reside in the thymus of these mice. The pool of long-lived Treg cells in the thymus was sustained by retention of Treg cells in the thymus and by recirculation of peripheral Treg cells back into the thymus. These long-lived thymic Treg cells suppressed T-cell proliferation to an equivalent extent to splenic Treg cells. Together, these data demonstrate that long-lived Treg cells accumulate in the thymus by both retention and recirculation.


Subject(s)
Cell Proliferation , T-Lymphocytes, Regulatory/immunology , Aging/immunology , Animals , Mice , Mice, Knockout , Spleen/cytology , Spleen/immunology , T-Lymphocytes, Regulatory/cytology , Thymus Gland , Time Factors
7.
Sci Signal ; 6(303): ra101, 2013 Nov 26.
Article in English | MEDLINE | ID: mdl-24280042

ABSTRACT

Natural regulatory T (nT(reg)) cells are important for maintaining tolerance to self- and foreign antigens, and they are thought to develop from thymocytes that receive strong T cell receptor (TCR)-mediated signals in the thymus. TCR engagement leads to the activation of phospholipase C-γ1, which generates the lipid second messenger diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate. We used mice that lack the ζ isoform of DAG kinase (DGKζ), which metabolizes DAG to terminate its signaling, to enhance TCR-mediated signaling and identify critical signaling events in nT(reg) cell development. Loss of DGKζ resulted in increased numbers of thymic CD25(+)Foxp3(-)CD4(+) nT(reg) cell precursors and Foxp3(+)CD4(+) nT(reg) cells in a cell-autonomous manner. DGKζ-deficient T cells exhibited increased nuclear translocation of the nuclear factor κB subunit c-Rel, as well as enhanced extracellular signal-regulated kinase (ERK) phosphorylation in response to TCR stimulation, suggesting that these downstream pathways may contribute to nT(reg) cell development. Indeed, reducing c-Rel abundance or blocking ERK phosphorylation abrogated the increased generation of nTreg cells by DGKζ-deficient thymocytes. The extent of ERK phosphorylation correlated with TCR-mediated acquisition of Foxp3 in immature thymocytes in vitro. Furthermore, the development of nT(reg) cells was augmented in mice in which ERK activation was selectively enhanced in T cells. Together, these data suggest that DGKζ regulates the development of nT(reg) cells by limiting the extent of activation of the ERK and c-Rel signaling pathways.


Subject(s)
Cell Differentiation/immunology , Diacylglycerol Kinase/deficiency , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/immunology , T-Lymphocytes, Regulatory/cytology , Thymus Gland/immunology , Animals , Blotting, Western , CD4 Antigens/metabolism , Diacylglycerol Kinase/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Flow Cytometry , Forkhead Transcription Factors/metabolism , Interleukin-2 Receptor alpha Subunit/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation , Proto-Oncogene Proteins c-rel/metabolism , T-Lymphocytes, Regulatory/immunology , Thymus Gland/cytology
8.
J Autoimmun ; 44: 13-20, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23834842

ABSTRACT

Strategies to expand regulatory T cells hold therapeutic potential for ameliorating T cell-mediated autoimmunity. Recently, we reported that the requirements for T cell receptor signaling in conventional T cell and regulatory T cell proliferation are different. Using mutant mice that display defective T cell receptor-mediated phospholipase Cγ (PLCγ) activation, we hereby demonstrate that PLCγ activation is required for antigen-specific conventional T cell proliferation but not for IL-2-induced regulatory T cell proliferation. This led us to hypothesize that in conjunction with IL-2, pharmacological inhibition of T cell receptor-mediated PLCγ activation might offer a novel therapeutic strategy to expand regulatory T cells while simultaneously inhibiting conventional T cell proliferation. Indeed, using the calcineurin inhibitor Cyclosporine A to inhibit signaling downstream of PLCγ, we found that Cyclosporine A attenuated antigen-specific Tconv proliferation but permitted IL-2-induced regulatory T cell expansion in vitro and in vivo. Furthermore, the combination of Cyclosporine A and IL-2 was superior over either Cyclosporine A or IL-2 monotherapy in protection against the T cell-mediated demyelinating autoimmune disease mouse model, experimental autoimmune encephalomyelitis. Thus, a combination of TCR signaling inhibition and IL-2 might be a beneficial strategy in expanding regulatory T cells and inhibiting conventional T cell proliferation in autoimmune settings.


Subject(s)
Interleukin-2/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Amino Acid Sequence , Animals , Autoimmunity/immunology , Cell Growth Processes/immunology , Cyclosporine/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Interleukin-2/metabolism , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/immunology , T-Lymphocytes, Regulatory/metabolism , Type C Phospholipases/immunology
9.
Am J Physiol Regul Integr Comp Physiol ; 301(5): R1479-85, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21849636

ABSTRACT

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9-39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7-36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.


Subject(s)
Appetite Depressants/pharmacology , Appetite Regulation/drug effects , Behavior, Animal/drug effects , Eating/drug effects , Glucagon-Like Peptide 1/pharmacology , Liver/innervation , Peptide Fragments/pharmacology , Receptors, Glucagon/agonists , Vagus Nerve/drug effects , Animals , Appetite Depressants/administration & dosage , Blood Glucose/drug effects , Blood Glucose/metabolism , Glucagon-Like Peptide 1/administration & dosage , Glucagon-Like Peptide-1 Receptor , Glucose Tolerance Test , Hormone Antagonists/pharmacology , Injections, Intraperitoneal , Male , Paracrine Communication , Peptide Fragments/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Glucagon/antagonists & inhibitors , Receptors, Glucagon/metabolism , Time Factors , Vagotomy , Vagus Nerve/metabolism , Vagus Nerve/surgery
10.
Am J Physiol Endocrinol Metab ; 300(6): E1002-11, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21406615

ABSTRACT

The adipose tissue-derived hormone leptin regulates energy balance through catabolic effects on central circuits, including proopiomelanocortin (POMC) neurons. Leptin activation of POMC neurons increases thermogenesis and locomotor activity. Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin signaling. POMC neuron-specific deletion of PTP1B in mice results in reduced high-fat diet-induced body weight and adiposity gain due to increased energy expenditure and greater leptin sensitivity. Mice lacking the leptin gene (ob/ob mice) are hypothermic and cold intolerant, whereas leptin delivery to ob/ob mice induces thermogenesis via increased sympathetic activity to brown adipose tissue (BAT). Here, we examined whether POMC PTP1B mediates the thermoregulatory response of CNS leptin signaling by evaluating food intake, body weight, core temperature (T(C)), and spontaneous physical activity (SPA) in response to either exogenous leptin or 4-day cold exposure (4°C) in male POMC-Ptp1b-deficient mice compared with wild-type controls. POMC-Ptp1b(-/-) mice were hypersensitive to leptin-induced food intake and body weight suppression compared with wild types, yet they displayed similar leptin-induced increases in T(C). Interestingly, POMC-Ptp1b(-/-) mice had increased BAT weight and elevated plasma triiodothyronine (T(3)) levels in response to a 4-day cold challenge, as well as reduced SPA 24 h after cold exposure, relative to controls. These data show that PTP1B in POMC neurons plays a role in short-term cold-induced reduction of SPA and may influence cold-induced thermogenesis via enhanced activation of the thyroid axis.


Subject(s)
Cold Temperature , Energy Metabolism/genetics , Energy Metabolism/physiology , Homeostasis/genetics , Homeostasis/physiology , Neurons/metabolism , Pro-Opiomelanocortin/physiology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/physiology , Animals , Ghrelin/blood , Hypothalamus/metabolism , Light , Mice , Mice, Knockout , Motor Activity/physiology , Neurons/physiology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/deficiency , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , RNA/biosynthesis , RNA/genetics , RNA/isolation & purification , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Ghrelin/biosynthesis , Signal Transduction/physiology , Telemetry , Thermogenesis/physiology , Thyroid Hormones/blood , Thyrotropin/metabolism
11.
Cell Metab ; 13(3): 320-30, 2011 Mar 02.
Article in English | MEDLINE | ID: mdl-21356521

ABSTRACT

Glucagon-like peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (fourth i.c.v.) GLP-1R activation by Exendin-4 (Ex-4) increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Ex-4, as inhibitors RpcAMP and U0126 (fourth i.c.v.), respectively, attenuated Ex-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (fourth i.c.v.). The PKA, MAPK, and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.


Subject(s)
Eating , Receptors, Glucagon/metabolism , Signal Transduction , Solitary Nucleus/metabolism , AMP-Activated Protein Kinase Kinases , Animals , Body Weight/drug effects , Butadienes/pharmacology , Cyclic AMP-Dependent Protein Kinases/genetics , Cyclic AMP-Dependent Protein Kinases/metabolism , Exenatide , Glucagon-Like Peptide-1 Receptor , Male , Mitogen-Activated Protein Kinase Kinases/metabolism , Nitriles/pharmacology , Peptides/pharmacology , Phosphorylation , Protein Kinases/metabolism , Rats , Rats, Sprague-Dawley , Venoms/pharmacology
12.
Endocrinology ; 152(6): 2400-8, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21447632

ABSTRACT

Fever and anorexia are induced by immune system challenges. Because these responses are adaptive when short lasting but deleterious when prolonged, an understanding of the mediating neural circuitry is important. Prostaglandins (PGE) are a critical signaling element for these immune responses. Despite the widespread distribution of PGE receptors throughout the brain, research focuses on the hypothalamic preoptic area as the mediating site of PGE action. Paraventricular nucleus of the hypothalamus (PVH), parabrachial nucleus (PBN), and nucleus tractus solitarius (NTS) neurons also express PGE receptors and are activated during systemic pathogen infection. A role for these neurons in PGE-induced fever, tachycardia, and anorexia is unexplored and is the subject of this report. A range of PGE2 doses was microinjected into third or fourth ventricles (v), or directly into the dorsal PVH, lateral PBN, and medial NTS, and core and brown adipose tissue temperature, heart rate, locomotor activity, and food intake were measured in awake, behaving rats. PGE2 delivery to multiple brain sites (third or fourth v, PVH, or PBN) induced a short- latency (< 10 min) fever and tachycardia. By contrast, an anorexic effect was observed only in response to third v and PVH stimulation. NTS PGE2 stimulation was without effect; locomotor activity was not affected for any of the sites. The data are consistent with a view of PGE2-induced effects as mediated by anatomically distributed sites rather than a single center. The data also underscore a potential anatomical dissociation of the neural pathways mediating pyrogenic and anorexic effects of PGE2.


Subject(s)
Anorexia/metabolism , Dinoprostone/metabolism , Fever/metabolism , Hypothalamus/metabolism , Neural Pathways/physiopathology , Tachycardia/metabolism , Animals , Anorexia/physiopathology , Disease Models, Animal , Fever/physiopathology , Heart Rate , Humans , Hypothalamus/anatomy & histology , Hypothalamus/physiopathology , Male , Neural Pathways/metabolism , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Prostaglandin E/metabolism , Tachycardia/physiopathology
13.
Cell Metab ; 11(1): 77-83, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20074530

ABSTRACT

Medial nucleus tractus solitarius (mNTS) neurons express leptin receptors (LepRs), and intra-mNTS delivery of leptin reduces food intake and body weight. Here, the contribution of endogenous LepR signaling in mNTS neurons to energy balance control was examined. Knockdown of LepR in mNTS and area postrema (AP) neurons of rats (LepRKD) via adeno-associated virus short hairpin RNA-interference (AAV-shRNAi) resulted in significant hyperphagia for chow, high-fat, and sucrose diets, yielding increased body weight and adiposity. The chronic hyperphagia of mNTS/AP LepRKD rats is likely mediated by a reduction in leptin potentiation of gastrointestinal satiation signaling, as LepRKD rats showed decreased sensitivity to the intake-reducing effects of cholecystokinin. LepRKD rats showed increased basal AMP-kinase activity in mNTS/AP micropunches, and pharmacological data suggest that this increase provides a likely mechanism for their chronic hyperphagia. Overall these findings demonstrate that LepRs in mNTS and AP neurons are required for normal energy balance control.


Subject(s)
Area Postrema/metabolism , Receptors, Leptin/metabolism , Solitary Nucleus/metabolism , AMP-Activated Protein Kinases/metabolism , Animals , Body Weight , Eating , Energy Metabolism , Gene Knockdown Techniques , Male , RNA Interference , RNA, Small Interfering/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Leptin/genetics , Signal Transduction
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