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1.
iScience ; 25(6): 104400, 2022 Jun 17.
Article in English | MEDLINE | ID: mdl-35637736

ABSTRACT

Pregnancy stimulates an intricately coordinated assortment of physiological changes to accommodate growth of the developing fetus, while simultaneously averting rejection of genetically foreign fetal cells and tissues. Despite increasing evidence that expansion of immune-suppressive maternal regulatory T cells enforces fetal tolerance and protects against pregnancy complications, the pregnancy-associated signals driving this essential adaptation remain poorly understood. Here we show that the female reproductive hormone, progesterone, coordinates immune tolerance by stimulating expansion of FOXP3+ regulatory T cells. Conditional loss of the canonical nuclear progesterone receptor in maternal FOXP3+ regulatory T cells blunts their proliferation and accumulation, which is associated with fetal wastage and decidual infiltration of activated CD8+ T cells. Reciprocally, the synthetic progestin 17α-hydroxyprogesterone caproate (17-OHPC) administered to pregnant mice reinforces fetal tolerance and protects against fetal wastage. These immune modulatory effects of progesterone that promote fetal tolerance establish a molecular link between immunological and other physiological adaptions during pregnancy.

2.
Int Immunopharmacol ; 77: 105914, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31634789

ABSTRACT

Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic inflammation and joint destruction. Although biological inhibitors such as TNF-α and IL-6 antibodies have achieved success in clinical therapy, small molecule inhibitors against the Janus kinases (JAKs) involved in the signaling pathways of various cytokine receptors have gained more attraction as safe and efficacious options. In this study, we identified CS12192 as a novel selective JAK3/JAK1/TBK1 inhibitor and investigated its pharmacological effects on the experimental arthritis models in rat and mouse. We found that CS12192 showed a more selective inhibitory activity on JAK3, and to a less extent on JAK1 and TBK1, that were verified by decreased activation of p-STATs and p-IRF3 as well as down-regulation of IFN gene expression in the cultured cells with relevant stimuli. Furthermore, oral treatment with CS12192 dose-dependently ameliorated the disease severity, hind paw swelling, body weight loss, and bone destruction in rat models of adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In a mouse CIA model, CS12192 also attenuated the disease severity, which was correlated with the suppressed CD4+ T cell activation and Th17 function, as well as the reduced cytokine levels in sera and pro-inflammatory cytokine and chemokine gene expression in joint tissue. Corroboratively, RANKL-induced osteoclast formation was inhibited by CS12192. Thus, these results suggest that CS12192 as a novel selective JAK inhibitor has therapeutic potential for the treatment of RA and may provide a new strategy for the control of autoimmune diseases.


Subject(s)
Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , Cytokines/blood , Cytokines/genetics , Female , Humans , Mice , Mice, Inbred DBA , Osteoclasts/drug effects , Protein Kinase Inhibitors/pharmacology , RAW 264.7 Cells , Rats, Inbred Lew , THP-1 Cells
3.
Anticancer Drugs ; 30(9): 909-916, 2019 10.
Article in English | MEDLINE | ID: mdl-30998512

ABSTRACT

As a novel orally active multitarget small molecule inhibitor, CS2164 has shown broad antitumor activities against several human tumor xenograft models in immune-compromised mice. However, the ability of CS2164 to modulate antitumor immunity in an immune-competent mouse tumor model remains undefined, although antiangiogenic treatment has been reported to affect immune cell infiltration and remodel the tumor immune microenvironment. In the present study, the subcutaneous and ascites hepatocellular carcinoma (HCC) models in syngeneic Balb/c mice established by inoculation of an H22 hepatoma cell line were utilized to investigate the antitumor and immunomodulatory effects of CS2164. Although the antitumor effects of CS2164 were validated in both subcutaneous and ascites HCC models in syngeneic mice, CS2164 treatment consistently modulated immune cell populations, both in the periphery and in tumor microenvironments, with upregulation of CD4 and CD8 T cells in the spleen, but downregulation of immunosuppressive populations including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages in the spleen and tumor tissues. Furthermore, CS2164 increased the relative gene expression and protein production of several proinflammatory cytokines in tumor-related ascites. These results indicate that CS2164 exerts an antitumor effect associated with its immunomodulatory activities in mouse HCC models, and may also provide evidence for the immunotherapy potentiation of CS2164 in future cancer treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Immunologic Factors/pharmacology , Liver Neoplasms/drug therapy , Naphthalenes/pharmacology , Quinolines/pharmacology , Angiogenesis Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Ascites/drug therapy , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Down-Regulation/drug effects , Female , Gene Expression/drug effects , Humans , Immunotherapy/methods , Macrophages/drug effects , Mice , Mice, Inbred BALB C , Tumor Microenvironment/drug effects , Up-Regulation/drug effects , Xenograft Model Antitumor Assays/methods
4.
Cancer Sci ; 108(3): 469-477, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28004478

ABSTRACT

Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer.


Subject(s)
Adenocarcinoma/drug therapy , Angiogenesis Inhibitors/therapeutic use , Colonic Neoplasms/drug therapy , M Phase Cell Cycle Checkpoints/drug effects , Mitosis/drug effects , Neovascularization, Pathologic/drug therapy , Phenylenediamines/therapeutic use , Quinolines/therapeutic use , 3T3 Cells , Animals , Aurora Kinase B/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Histones/metabolism , Humans , Inflammation/drug therapy , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Docking Simulation , Naphthalenes , Phosphorylation/drug effects , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Xenograft Model Antitumor Assays
5.
Cell Rep ; 17(7): 1783-1794, 2016 11 08.
Article in English | MEDLINE | ID: mdl-27829150

ABSTRACT

Self-reactive CD4 T cells are incompletely deleted during thymic development, and their peripheral seeding highlights the need for additional safeguards to avert autoimmunity. Here, we show an essential role for the coinhibitory molecule programmed death-1 (PD-1) in silencing the activation of high-affinity autoreactive CD4 T cells. Each wave of self-reactive CD4 T cells that escapes thymic deletion autonomously upregulates PD-1 to maintain self-tolerance. By tracking the progeny derived from individual autoreactive CD4 T cell clones, we demonstrate that self-reactive cells with the greatest autoimmune threat and highest self-antigen affinity express the most PD-1. Reciprocally, PD-1 deprivation unleashes high-affinity self-reactive CD4 T cells in target tissues to exacerbate neuronal inflammation and autoimmune diabetes. Reliance on PD-1 to actively maintain self-tolerance may explain why exploiting this pathway by cancerous cells and invasive microbes efficiently subverts protective immunity, and why autoimmune side effects can develop after PD-1-neutralizing checkpoint therapies.


Subject(s)
Autoimmunity , CD4-Positive T-Lymphocytes/immunology , Programmed Cell Death 1 Receptor/metabolism , Animals , Autoantigens/immunology , Cell Proliferation , Clone Cells , Lymphocyte Activation/immunology , Mice, Inbred C57BL , Receptors, Antigen, T-Cell/metabolism , Self Tolerance/immunology
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(2): 457-62, 2016 Apr.
Article in Chinese | MEDLINE | ID: mdl-27151010

ABSTRACT

OBJECTIVE: To analyze the clinical course of a very elderly patient with advanced diffuse large B cell lymphoma (DLBCL), so as to explore the incidence, prognosis and treatment of DLBCL and to analyse the prognostic and therapeutic significance of molecular subtype. METHODS: The clinical history, auxiliary examinations, clinical diagnostic standards, therapeutic methods, biopsy and autopsy of this patient were retrospectively analyzed; the incidence, current treatment status, molecular biological features, and prognostic and therapeutic significance of molecular subtype were studied. RESULTS: After admission, this patient was diagnosed as non-GCB DLBCL, NOS, stage IV B and in the high risk group (IPI = 5, ECOG = 2). She achieved a decent partial response after many times of imunochemotherapy, but his disease status soon progressed. The liver occupying biopsy revealed non-GCB, while the spleen tumor pathology revealed GCB; pathological typing of these two methods was completely opposite. Autopsy pathological diagnosis showed that the death causes included extensive tumor metastasis, dyscrasia and respiratory circle failure. CONCLUSION: Incidence of aged patients with DLBCL is high, and the disease is aggressive; the treatment is low responsive and difficult, and new therapeutic methods are needed. Gene expression profile (GEP) can provide molecular subtype and potential pathogenic mechanism, which can promote the development of new targeted therapy and individualized treatment.


Subject(s)
Lymphoma, Large B-Cell, Diffuse/diagnosis , Aged , Female , Humans , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Neoplasm Staging , Prognosis
7.
Chem Sci ; 7(4): 2888-2895, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-30090282

ABSTRACT

Though urgently needed, high-performance near-infrared organic light-emitting diodes (NIR-OLEDs) are still rare. NIR-OLEDs based on conventional NIR fluorescent materials usually suffer from low external quantum efficiencies (EQEs) because of the intrinsic obstacles according to the spin-statistics limit and energy-gap law. Herein, we realized high-efficiency and low efficiency roll-off fluorescent NIR-OLEDs through efficient triplet fusion of a bipolar host doped with a special naphthoselenadiazole emitter (4,9-bis(4-(2,2-diphenylvinyl)phenyl)-naphtho[2,3-c][1,2,5]selenadiazole, NSeD). Unlike typical NIR organic donor-acceptor (D-A) chromophores, NSeD features a non-D-A structure and a very large HOMO/LUMO overlap and displays a strong deep-red to NIR fluorescence and unique ambipolar character. The corresponding photoluminescence quantum efficiency of NSeD reaches 52% in solution and retains 17% in the blend film. The optimized NIR-OLEDs demonstrated a strong emission at 700 nm, a high maximum EQE of 2.1% (vs. the predicted theoretical maximum efficiency of 1.3%) and the EQE remained at around 2% over a wide range of current densities from 18 to 200 mA cm-2, which is amongst the highest performance for NIR-OLEDs based on organic fluorescent materials.

8.
Chimerism ; 6(1-2): 8-20, 2015 Apr 03.
Article in English | MEDLINE | ID: mdl-26517600

ABSTRACT

Compulsory exposure to genetically foreign maternal tissue imprints in offspring sustained tolerance to noninherited maternal antigens (NIMA). Immunological tolerance to NIMA was first described by Dr. Ray D. Owen for women genetically negative for erythrocyte rhesus (Rh) antigen with reduced sensitization from developmental Rh exposure by their mothers. Extending this analysis to HLA haplotypes has uncovered the exciting potential for therapeutically exploiting NIMA-specific tolerance naturally engrained in mammalian reproduction for improved clinical outcomes after allogeneic transplantation. Herein, we summarize emerging scientific concepts stemming from tolerance to NIMA that includes postnatal maintenance of microchimeric maternal origin cells in offspring, expanded accumulation of immune suppressive regulatory T cells with NIMA-specificity, along with teleological benefits and immunological consequences of NIMA-specific tolerance conserved across mammalian species.


Subject(s)
HLA Antigens/immunology , Immune Tolerance , Immunologic Memory , Rh-Hr Blood-Group System/immunology , T-Lymphocytes, Regulatory/immunology , Animals , HLA Antigens/history , History, 20th Century , History, 21st Century , Humans , Rh-Hr Blood-Group System/history
9.
Aging Cell ; 14(6): 1122-6, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26248606

ABSTRACT

Aging confers increased susceptibility to common pathogens including influenza A virus. Despite shared vulnerability to infection with advancing age in humans and rodents, the relatively long time required for immune senescence to take hold practically restricts the use of naturally aged mice to investigate aging-induced immunological shifts. Here, we show accelerated aging Lmna(Dhe) mice with spontaneous mutation in the nuclear scaffolding protein, lamin A, replicate infection susceptibility, and substantial immune cell shifts that occur with advancing age. Naturally aged (≥ 20 month) and 2- to 3-month-old Lmna(Dhe) mice share near identically increased influenza A susceptibility compared with age-matched Lmna(WT) control mice. Increased mortality and higher viral burden after influenza infection in Lmna(Dhe) mice parallel reduced accumulation of lung alveolar macrophage cells, systemic expansion of immune suppressive Foxp3⁺ regulatory T cells, and skewed immune dominance among viral-specific CD8⁺T cells similar to the immunological phenotype of naturally aged mice. Thus, aging-induced infection susceptibility and immune senescence are replicated in accelerated aging Lmna(Dhe) mice.


Subject(s)
Aging/immunology , Influenza A Virus, H1N1 Subtype/immunology , Lung/immunology , Orthomyxoviridae Infections/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Disease Models, Animal , Disease Susceptibility/immunology , Lamin Type A/genetics , Lung/virology , Macrophages, Alveolar/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Progeria/genetics , Progeria/immunology , T-Lymphocytes, Regulatory/immunology
10.
Cell ; 162(3): 505-15, 2015 Jul 30.
Article in English | MEDLINE | ID: mdl-26213383

ABSTRACT

Exposure to maternal tissue during in utero development imprints tolerance to immunologically foreign non-inherited maternal antigens (NIMA) that persists into adulthood. The biological advantage of this tolerance, conserved across mammalian species, remains unclear. Here, we show maternal cells that establish microchimerism in female offspring during development promote systemic accumulation of immune suppressive regulatory T cells (Tregs) with NIMA specificity. NIMA-specific Tregs expand during pregnancies sired by males expressing alloantigens with overlapping NIMA specificity, thereby averting fetal wastage triggered by prenatal infection and non-infectious disruptions of fetal tolerance. Therefore, exposure to NIMA selectively enhances reproductive success in second-generation females carrying embryos with overlapping paternally inherited antigens. These findings demonstrate that genetic fitness, canonically thought to be restricted to Mendelian inheritance, is enhanced in female placental mammals through vertically transferred maternal cells that promote conservation of NIMA and enforce cross-generational reproductive benefits.


Subject(s)
Fetus/immunology , Genetic Fitness , Immune Tolerance , Mammals/physiology , Pregnancy/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Antigens/immunology , Chimerism , Female , Humans , Male , Mammals/immunology , Mice , Placenta/immunology
12.
J Clin Invest ; 125(4): 1713-25, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25751061

ABSTRACT

Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua. Maternal CD8+ T cells with fetal specificity upregulated expression of the chemokine receptor CXCR3 and, together with neutrophils and macrophages, were essential for L. monocytogenes-induced fetal resorption. Conversely, decidual accumulation of maternal T cells with fetal specificity and fetal wastage were extinguished by CXCR3 blockade or in CXCR3-deficient mice. Remarkably, protection against fetal wastage and in utero L. monocytogenes invasion was maintained even when CXCR3 neutralization was initiated after infection, and this protective effect extended to fetal resorption triggered by partial ablation of immune-suppressive maternal Tregs, which expand during pregnancy to sustain fetal tolerance. Together, our results indicate that functionally overriding chemokine silencing at the maternal-fetal interface promotes the pathogenesis of prenatal infection and suggest that therapeutically reinforcing this pathway represents a universal approach for mitigating immune-mediated pregnancy complications.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Fetal Death/prevention & control , Listeriosis/immunology , Pregnancy Complications, Infectious/immunology , Receptors, CXCR3/physiology , T-Lymphocyte Subsets/immunology , Adoptive Transfer , Ampicillin/therapeutic use , Animals , Anti-Bacterial Agents/therapeutic use , Chemokine CXCL9/biosynthesis , Chemokine CXCL9/genetics , Chemokine CXCL9/physiology , Chemokines/metabolism , Crosses, Genetic , Decidua/immunology , Female , Fetal Death/etiology , Fetal Resorption/immunology , Fetal Resorption/prevention & control , Listeriosis/drug therapy , Macrophages/immunology , Male , Maternal-Fetal Exchange , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Neutrophils/immunology , Ovalbumin/genetics , Ovalbumin/immunology , Peptide Fragments/genetics , Peptide Fragments/immunology , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Receptors, CXCR3/antagonists & inhibitors , Receptors, CXCR3/biosynthesis , Receptors, CXCR3/deficiency , Receptors, CXCR3/genetics , Spleen/immunology , T-Cell Antigen Receptor Specificity , T-Lymphocytes, Regulatory/immunology , Up-Regulation , Virulence
13.
Cell Mol Immunol ; 11(6): 595-605, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25242275

ABSTRACT

Listeria monocytogenes (Lm) is an intracellular bacterium with unique predisposition for systemic maternal infection during pregnancy and morbid consequences for the developing fetus. Given the high mortality associated with prenatal Lm infection, strategies for augmenting protective immunity during the exceedingly vulnerable period of pregnancy are urgently needed. Herein, protection conferred by attenuated Lm administered before pregnancy against subsequent virulent Lm prenatal infection was evaluated. We show that protection against secondary Lm infection in non-pregnant mice is sharply moderated during allogeneic pregnancy because significantly more bacteria are recovered from maternal tissues, despite the numerical and functional preservation of pathogen-specific CD8(+) T cells. More importantly, preconceptual priming does not protect against in utero invasion or fetal wastage because mice inoculated with attenuated Lm prior to pregnancy and naive pregnant controls each showed near complete fetal resorption and pathogen recovery from individual concepti after Lm infection during pregnancy. Remarkably, the lack of protection against prenatal Lm infection with preconceptual priming in allogeneic pregnancy is restored during syngeneic pregnancy. Thus, maternal-fetal antigen discordance dictates the ineffectiveness of preconceptual vaccination against fetal complications after prenatal Lm infection, despite the numerical and functional preservation of pathogen-specific CD8(+) T cells.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Listeria monocytogenes/physiology , Listeriosis/immunology , Prenatal Exposure Delayed Effects/prevention & control , Vaccines, Attenuated , Animals , Disease Susceptibility , Female , Histocompatibility , Humans , Isoantigens/immunology , Listeriosis/complications , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Preconception Care , Pregnancy/immunology , Prenatal Exposure Delayed Effects/etiology , Prenatal Exposure Delayed Effects/immunology , Vaccination , Vaccines, Attenuated/administration & dosage
14.
Proc Natl Acad Sci U S A ; 111(29): 10672-7, 2014 Jul 22.
Article in English | MEDLINE | ID: mdl-25002484

ABSTRACT

The costimulatory B7-1 (CD80)/B7-2 (CD86) molecules, along with T-cell receptor stimulation, together facilitate T-cell activation. This explains why in vivo B7 costimulation neutralization efficiently silences a variety of human autoimmune disorders. Paradoxically, however, B7 blockade also potently moderates accumulation of immune-suppressive regulatory T cells (Tregs) essential for protection against multiorgan systemic autoimmunity. Here we show that B7 deprivation in mice overrides the necessity for Tregs in averting systemic autoimmunity and inflammation in extraintestinal tissues, whereas peripherally induced Tregs retained in the absence of B7 selectively mitigate intestinal inflammation caused by Th17 effector CD4(+) T cells. The need for additional immune suppression in the intestine reflects commensal microbe-driven T-cell activation through the accessory costimulation molecules ICOSL and OX40L. Eradication of commensal enteric bacteria mitigates intestinal inflammation and IL-17 production triggered by Treg depletion in B7-deficient mice, whereas re-establishing intestinal colonization with Candida albicans primes expansion of Th17 cells with commensal specificity. Thus, neutralizing B7 costimulation uncovers an essential role for Tregs in selectively averting intestinal inflammation by Th17 CD4(+) T cells with commensal microbe specificity.


Subject(s)
B7-1 Antigen/metabolism , B7-2 Antigen/metabolism , CD4-Positive T-Lymphocytes/immunology , Inducible T-Cell Co-Stimulator Ligand/metabolism , Inflammation/immunology , Interleukin-17/biosynthesis , Intestines/pathology , OX40 Ligand/metabolism , Animals , CD4-Positive T-Lymphocytes/cytology , CTLA-4 Antigen/metabolism , Candida albicans/physiology , Cell Differentiation/immunology , Cell Proliferation , Humans , Inflammation/microbiology , Inflammation/pathology , Intestines/immunology , Intestines/microbiology , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Phenotype , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology
15.
J Immunol ; 192(11): 4949-56, 2014 Jun 01.
Article in English | MEDLINE | ID: mdl-24837152

ABSTRACT

The immunological alterations required for successful pregnancy in eutherian placental mammals have remained a scientific enigma since the discovery of MHC haplotype diversity and unique immune signatures among individuals. Within the past 10 years, accumulating data suggest that immune-suppressive regulatory T cells (Tregs) confer essential protective benefits in sustaining tolerance to the semiallogeneic fetus during pregnancy, along with their more established roles in maintaining tolerance to self and "extended self" commensal Ags that averts autoimmunity. Reciprocally, many human pregnancy complications stemming from inadequacies in fetal tolerance have been associated with defects in maternal Tregs. Thus, further elucidating the immunological shifts during pregnancy not only have direct translational implications for improving perinatal health, they have enormous potential for unveiling new clues about how Tregs work in other biological contexts. In this article, epidemiological data in human pregnancy and complementary animal studies implicating a pivotal protective role for maternal Tregs are summarized.


Subject(s)
Antigens/immunology , Immune Tolerance , Pregnancy Complications/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Female , Humans , Pregnancy , Pregnancy Complications/pathology , T-Lymphocytes, Regulatory/pathology
16.
J Immunol ; 192(7): 2970-4, 2014 Apr 01.
Article in English | MEDLINE | ID: mdl-24591368

ABSTRACT

Pregnancy stimulates induced Foxp3 expression among maternal CD4(+) T cells with fetal specificity. Although sustained maternal regulatory CD4(+) T cell (Treg) expansion is essential for maintaining fetal tolerance during pregnancy, the necessity for Foxp3(+) cells with fetal specificity remains undefined. In this study, we demonstrate that mitigating Treg differentiation among maternal CD4(+) T cells with a single surrogate fetal specificity elicits Ag-specific fetal loss. Using recombinant Listeria monocytogenes to prime stably differentiated Th1 CD4(+) T cells with fetal I-A(b):2W1S55-68 specificity refractory to pregnancy-induced Foxp3 expression, we show that Ag delivery by cytoplasmic L. monocytogenes causes selective loss of 2W1S(+) offspring through CD4 cell- and IFN-γ-dependent pathways. In contrast, CD4(+) T cells primed by L. monocytogenes restricted from the cell cytoplasm are markedly more plastic for induced Foxp3 expression, with normal pregnancy outcomes. Thus, committed Th1 polarization blocks pregnancy induced Treg differentiation among maternal CD4(+) T cells with fetal specificity and triggers Ag-specific fetal loss.


Subject(s)
Antigens/immunology , CD4-Positive T-Lymphocytes/immunology , Fetus/immunology , Forkhead Transcription Factors/immunology , Th1 Cells/immunology , Adoptive Transfer , Animals , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/transplantation , Cell Differentiation/immunology , Female , Fetus/metabolism , Flow Cytometry , Forkhead Transcription Factors/metabolism , Host-Pathogen Interactions/immunology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Listeria monocytogenes/immunology , Listeria monocytogenes/physiology , Listeriosis/immunology , Listeriosis/microbiology , Mice , Mice, Congenic , Mice, Inbred BALB C , Mice, Inbred C57BL , Pregnancy , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th1 Cells/metabolism
17.
Chimerism ; 5(1): 16-9, 2014.
Article in English | MEDLINE | ID: mdl-24553046

ABSTRACT

Long-term maintenance of immune components with defined specificity, without antigen is the hallmark feature of immunological memory. However, there are fundamental differences in how memory CD8(+) compared with CD4(+) T cells are maintained. After complete antigen elimination, CD8(+) T cells can persist as a self-renewing numerically stable cell population, and therefore satisfy the most stringent definition of "memory." Comparatively, CD4(+) T cell maintenance is considerably less stable, often requiring low-level antigen persistence or antigenic reminders. Recent studies show these basic memory features, classically ascribed to effector CD8(+) and CD4(+) T cells, extend to immune suppressive Foxp3(+) regulatory CD4(+) T cells (Tregs). In particular, gestational expansion and postpartum retention of maternal Tregs with fetal specificity may explain the protective benefits of primary pregnancy on complications in subsequent pregnancy. Herein, the possibility of ongoing antigenic reminders from fetal cell microchimerism in postpartum maintenance of maternal Tregs with fetal specificity is considered.


Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Chimera/immunology , Immunologic Memory , Maternal-Fetal Exchange , T-Lymphocytes, Regulatory/metabolism , Animals , CD8-Positive T-Lymphocytes/immunology , Embryo, Mammalian , Female , Humans , Pregnancy , T-Lymphocytes, Regulatory/immunology
18.
Nature ; 504(7478): 158-62, 2013 Dec 05.
Article in English | MEDLINE | ID: mdl-24196717

ABSTRACT

Newborn infants are highly susceptible to infection. This defect in host defence has generally been ascribed to the immaturity of neonatal immune cells; however, the degree of hyporesponsiveness is highly variable and depends on the stimulation conditions. These discordant responses illustrate the need for a more unified explanation for why immunity is compromised in neonates. Here we show that physiologically enriched CD71(+) erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after co-culture with neonatal splenocytes. Neonatal CD71(+) cells express the enzyme arginase-2, and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with L-arginine overrides immunosuppression. In addition, the ablation of CD71(+) cells in neonatal mice, or the decline in number of these cells as postnatal development progresses parallels the loss of suppression, and restored resistance to the perinatal pathogens Listeria monocytogenes and Escherichia coli. However, CD71(+) cell-mediated susceptibility to infection is counterbalanced by CD71(+) cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition. Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Thus, CD71(+) cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. This finding challenges the idea that the susceptibility of neonates to infection reflects immune-cell-intrinsic defects and instead highlights processes that are developmentally more essential and inadvertently mitigate innate immune protection. We anticipate that these results will spark renewed investigation into the need for immunosuppression in neonates, as well as improved strategies for augmenting host defence in this vulnerable population.


Subject(s)
Antigens, CD/metabolism , Erythroid Cells/immunology , Escherichia coli Infections/immunology , Immune Tolerance/immunology , Listeriosis/immunology , Receptors, Transferrin/metabolism , Animals , Animals, Newborn , Arginase/genetics , Arginase/metabolism , Disease Susceptibility/immunology , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Erythroid Cells/enzymology , Escherichia coli/immunology , Female , Fetal Blood/cytology , Humans , Immune Tolerance/drug effects , Immune Tolerance/genetics , Listeria monocytogenes/immunology , Male , Mice , Mice, Inbred C57BL , Tumor Necrosis Factor-alpha/metabolism
19.
Reproduction ; 146(6): R191-203, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23929902

ABSTRACT

Pregnancy in placental mammals offers exceptional comprehensive benefits of in utero protection, nutrition, and metabolic waste elimination for the developing fetus. However, these benefits also require durable strategies to mitigate maternal rejection of fetal tissues expressing foreign paternal antigens. Since the initial postulate of expanded maternal immune tolerance by Sir Peter Medawar 60 years ago, an amazingly elaborate assortment of molecular and cellular modifications acting both locally at the maternal-placental interface and systemically have been shown to silence potentially detrimental maternal immune responses. In turn, simultaneously maintaining host defense against the infinite array of potential pathogens during pregnancy is equally important. Fortunately, resistance against most infections is preserved seamlessly throughout gestation. On the other hand, recent studies on pathogens with unique predisposition for prenatal infections have uncovered distinctive holes in host defense associated with the reproductive process. Using these infections to probe the response during pregnancy, the immune suppressive regulatory subset of maternal CD4 T cells has been increasingly shown to dictate the inter-workings between prenatal infection susceptibility and pathogenesis of ensuing pregnancy complications. Herein, the recent literature suggesting a necessity for maternal regulatory T cells (Tregs) in pregnancy-induced immunological shifts that sustain fetal tolerance is reviewed. Additional discussion is focused on how expansion of maternal Treg suppression may become exploited by pathogens that cause prenatal infections and the perilous potential of infection-induced immune activation that may mitigate fetal tolerance and inadvertently inject hostility into the protective in utero environment.


Subject(s)
Pregnancy Complications, Infectious/immunology , Pregnancy/immunology , T-Lymphocytes, Regulatory/physiology , Female , Fetal Diseases/immunology , Fetus/immunology , Humans , Immune Tolerance/immunology , Immunity, Innate/physiology
20.
J Leukoc Biol ; 94(2): 367-76, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23744647

ABSTRACT

Although T cell activation has been classically described to require distinct, positive stimulation signals that include B7-1 (CD80) and B7-2 (CD86) costimulation, overriding suppression signals that avert immune-mediated host injury are equally important. How these opposing stimulation and suppression signals work together remains incompletely defined. Our recent studies demonstrate that CD8 Teff activation in response to cognate peptide stimulation is actively suppressed by the Foxp3(+) subset of CD4 cells, called Tregs. Here, we show that the elimination of Treg suppression does not bypass the requirement for positive B7-1/B7-2 costimulation. The expansion, IFN-γ cytokine production, cytolytic, and protective features of antigen-specific CD8 T cells stimulated with purified cognate peptide in Treg-ablated mice were each neutralized effectively by CTLA-4-Ig that blocks B7-1/B7-2. In turn, given the efficiency whereby CTLA-4-Ig overrides the effects of Treg ablation, the role of Foxp3(+) cell-intrinsic CTLA-4 in mitigating CD8 Teff activation was also investigated. With the use of mixed chimera mice that contain CTLA-4-deficient Tregs exclusively after the ablation of WT Foxp3(+) cells, a critical role for Treg CTLA-4 in suppressing the expansion, cytokine production, cytotoxicity, and protective features of peptide-stimulated CD8 T cells is revealed. Thus, the activation of protective CD8 T cells requires positive B7-1/B7-2 costimulation even when suppression by Tregs and in particular, Treg-intrinsic CTLA-4 is circumvented.


Subject(s)
B7-1 Antigen/antagonists & inhibitors , B7-2 Antigen/antagonists & inhibitors , CD8-Positive T-Lymphocytes/immunology , Lymphocyte Activation , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Abatacept , Adoptive Transfer , Animals , B7-1 Antigen/deficiency , B7-1 Antigen/physiology , B7-2 Antigen/deficiency , B7-2 Antigen/physiology , Cytotoxicity, Immunologic , Forkhead Transcription Factors/analysis , Immunoconjugates/pharmacology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Ovalbumin/immunology , Peptide Fragments/immunology , Radiation Chimera
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