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1.
Diabetes ; 69(11): 2400-2413, 2020 11.
Article in English | MEDLINE | ID: mdl-32843568

ABSTRACT

Low-dose interleukin-2 (IL-2) represents a new therapeutic approach to regulate immune homeostasis to promote immune tolerance in patients with autoimmune diseases, including type 1 diabetes. We have developed a new IL-2-based biologic, an IL-2/CD25 fusion protein, with greatly improved pharmacokinetics and pharmacodynamics when compared with recombinant IL-2 to enhance this type of immunotherapy. In this study, we show that low-dose mouse IL-2/CD25 (mIL-2/CD25), but not an equivalent amount of IL-2, prevents the onset of diabetes in NOD mice and controls diabetes in hyperglycemic mice. mIL-2/CD25 acts not only to expand regulatory T cells (Tregs) but also to increase their activation and migration into lymphoid tissues and the pancreas. Lower incidence of diabetes is associated with increased serum levels of IL-10, a cytokine readily produced by activated Tregs. These effects likely act in concert to lower islet inflammation while increasing Tregs in the remaining inflamed islets. mIL-2/CD25 treatment is also associated with lower anti-insulin autoantibody levels in part by inhibition of T follicular helper cells. Thus, long-acting mIL-2/CD25 represents an improved IL-2 analog that persistently elevates Tregs to maintain a favorable Treg/effector T cell ratio that limits diabetes by expansion of activated Tregs that readily migrate into lymphoid tissues and the pancreas while inhibiting autoantibodies.


Subject(s)
Diabetes Mellitus/metabolism , Interleukin-2 Receptor alpha Subunit , Interleukin-2/pharmacology , Receptors, Interleukin-2/metabolism , Signal Transduction/physiology , Animals , Autoantibodies , Female , Humans , Interleukin-2/chemistry , Mice , Mice, Inbred Strains , Recombinant Fusion Proteins/pharmacology , T-Lymphocyte Subsets/drug effects
2.
Nat Commun ; 10(1): 1037, 2019 03 04.
Article in English | MEDLINE | ID: mdl-30833563

ABSTRACT

IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution of IL-2 during Treg thymic development, peripheral homeostasis and lineage stability remains unclear. Here we show that IL-2R signaling is required by thymic Tregs at an early step for expansion and survival, and a later step for functional maturation. Using inducible, conditional deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling is indispensable for Treg homeostasis, whereas Treg lineage stability is largely IL-2-independent. CD25 knockout peripheral Tregs have increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2R transcriptional signature is noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, while peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.


Subject(s)
Homeostasis , Interleukin-2 Receptor beta Subunit/metabolism , Organogenesis , Signal Transduction , T-Lymphocytes, Regulatory/metabolism , Thymus Gland/growth & development , Animals , Apoptosis , Biosynthetic Pathways , Cytokines/metabolism , Female , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2 Receptor alpha Subunit/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Mitochondria/metabolism , Oxidative Stress , Phenotype , Skin/pathology , Thymus Gland/immunology
3.
J Exp Med ; 215(3): 841-858, 2018 03 05.
Article in English | MEDLINE | ID: mdl-29374027

ABSTRACT

Genetically predisposed CTLA4 insufficiency in humans is associated with gastric cancer development, which is paradoxical to the prototypical role of CTLA4 in suppressing antitumor immunity. CTLA4 is a critical immune checkpoint against autoimmune disorders. Autoimmunity has been implicated in protumor or antitumor activities. Here, we show that CTLA4 insufficiency initiates de novo tumorigenesis in the mouse stomach through inflammation triggered by host-intrinsic immune dysregulation rather than microbiota, with age-associated progression to malignancy accompanied by epigenetic dysregulation. The inflammatory tumorigenesis required CD4 T cells, but not the TH1 or TH17 subsets. Deficiencies in IL-4 and IL-13 or IL-4 receptor α broke the link between inflammation and initiation of tumorigenesis. This study establishes the causality of CTLA4 insufficiency in gastric cancer and uncovers a role of type 2 inflammation in initiating gastric epithelial transformation. These findings suggest possible improvement of immune therapies by blocking tumorigenic type 2 inflammation while preserving antitumor type 1 immunity.


Subject(s)
CTLA-4 Antigen/deficiency , Carcinogenesis/pathology , Cytokines/metabolism , Inflammation/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Antibodies/pharmacology , Autoimmunity , Carcinogenesis/metabolism , Epigenesis, Genetic , Humans , Inflammation/metabolism , Intercellular Signaling Peptides and Proteins , Interferon-gamma/metabolism , Interleukins/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Microbiota , Peptides , Precancerous Conditions/pathology , RNA Interference , Stomach/pathology , Stomach Neoplasms/metabolism , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathology , Th1 Cells/immunology , Th17 Cells/immunology
4.
Gut Microbes ; 7(1): 40-7, 2016.
Article in English | MEDLINE | ID: mdl-26939850

ABSTRACT

Microbiota has been shown to promote tolerogenic differentiation of T lymphocytes. It remains unclear to what extent microbiota triggers de novo re-programming or amplify pre-existing plasticity intrinsic to T cells. In a study with mouse models to track the clonal fate of CD4 and CD8 T cells, we discovered that CD8 T cells converted to MHC class I-restricted CD4 T cells without regard to selfness of their antigen specificity. In mesenteric lymph nodes (MLN), CD8 T cells converted to CD4(+)Foxp3(+) regulatory T (Treg) cells which were enriched in the large intestine lamina propria (LILP) and suppressed chemical- or immune-mediated inflammatory damage. In germ-free conditions, the converted CD4 populations were present in MLN, but absent in LILP. Therefore, an intrinsic plasticity in the host was amplified by the gut microbiota, leading to selfless tolerance induction in the intestinal mucosa. The findings may be relevant to HIV infection, cancer and autoimmune disorders.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation/immunology , Cell Lineage/immunology , Gastrointestinal Microbiome/immunology , Immune Tolerance/immunology , Symbiosis/immunology , Adaptive Immunity/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Histocompatibility Antigens Class I/immunology , Lipopolysaccharides/immunology , Lymph Nodes/cytology , Lymph Nodes/immunology , Mice
5.
Cell Rep ; 10(4): 574-85, 2015 Feb 03.
Article in English | MEDLINE | ID: mdl-25640181

ABSTRACT

CD4 and CD8 T cell lineages differentiate through respective thymic selection processes. Here, we report cross-differentiation from the CD8 lineage to CD4 T cells, but not vice versa, predominantly in the large-intestine-associated microenvironment. It occurred in the absence or distal presence of cognate antigens. This pathway produced MHC-class-I-restricted CD4(+)Foxp3(+) T(reg) (CI-T(reg)) cells. Blocking T cell-intrinsic TGFß signaling diminished CI-Treg populations in lamina propria, but it did not preclude the CD8-to-CD4 conversion. Microbiota were not required for the cross-differentiation, but the presence of microbiota led to expansion of the converted CD4 T cell population in the large intestine. CI-T(reg) cells did not promote tolerance to microbiota per se, but they regulated systemic homeostasis of T lymphocytes and protected the large intestine from inflammatory damage. Overall, the clonal conversion from the CD8 lineage to CD4 T cell subsets occurred regardless of "self" or "nonself." This lineage plasticity may promote "selfless" tolerance for immune balance.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Microbiota/physiology , Animals , Colitis/immunology , Colitis/microbiology , Flow Cytometry , Intestines/microbiology , Mice , Mice, Knockout , Mice, Transgenic
6.
J Immunol ; 193(9): 4368-80, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25246499

ABSTRACT

Quantitative variations in CTLA4 expression, because of genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T cells (T(reg)) but also required for intrinsic control of conventional T (T(conv)) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting Treg function both in vivo and in vitro. It led to an increase in T(reg) memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNA interference or Ab blockade promoted conventional effector memory T cell formation in the T(conv) compartment. The CD4(+) conventional effector memory T cells, including those within target tissue, produced IL-17 or IFN-γ. Blocking IL-7 signaling reduced the Th17 autoimmune compartment but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both T(conv) and T(reg) lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, although the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T cell immunity while suppressing tissue damage.


Subject(s)
Autoimmunity , CTLA-4 Antigen/metabolism , Immunologic Memory , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Autoantigens/immunology , CTLA-4 Antigen/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Epitopes, T-Lymphocyte , Female , Gene Expression , Genetic Loci , H-2 Antigens/genetics , Immunohistochemistry , Immunophenotyping , Interferon-gamma/biosynthesis , Interleukin-17/biosynthesis , Male , Mice , Mice, Transgenic , Pancreas/immunology , Pancreas/metabolism , Pancreas/pathology , Phenotype , Receptors, Interleukin-17/antagonists & inhibitors , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism
7.
J Exp Med ; 211(3): 441-56, 2014 Mar 10.
Article in English | MEDLINE | ID: mdl-24567447

ABSTRACT

Real-time imaging studies are reshaping immunological paradigms, but a visual framework is lacking for self-antigen-specific T cells at the effector phase in target tissues. To address this issue, we conducted intravital, longitudinal imaging analyses of cellular behavior in nonlymphoid target tissues to illustrate some key aspects of T cell biology. We used mouse models of T cell-mediated damage and protection of pancreatic islet grafts. Both CD4(+) and CD8(+) effector T (Teff) lymphocytes directly engaged target cells. Strikingly, juxtaposed ß cells lacking specific antigens were not subject to bystander destruction but grew substantially in days, likely by replication. In target tissue, Foxp3(+) regulatory T (Treg) cells persistently contacted Teff cells with or without involvement of CD11c(+) dendritic cells, an observation conciliating with the in vitro "trademark" of Treg function, contact-dependent suppression. This study illustrates tolerance induction by contact-based immune cell interaction in target tissues and highlights potentials of tissue regeneration under antigenic incognito in inflammatory settings.


Subject(s)
Autoimmunity/immunology , Cell Communication/immunology , Islets of Langerhans Transplantation/immunology , T-Lymphocytes, Regulatory/immunology , Transplantation Tolerance/immunology , Adoptive Transfer , Analysis of Variance , Animals , Autoantigens/immunology , Bromodeoxyuridine , Crosses, Genetic , Fluorescence , Image Processing, Computer-Assisted/methods , Mice , Mice, Inbred C57BL , Mice, Transgenic , RNA Interference
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