Preconception immunization can modulate intracellular Th2 cytokine profile in offspring: in vivo influence of interleukin 10 and B/T cell collaboration

Transplantation of HLA mismatched hematopoietic stem cells in patients with severe combined immunodeficiency (SCID) can result in a selective engraftment of T cells of donor origin with complete immunologic reconstitution and in vivo tolerance. The latter may occur in the absence of clonal deletion of donor T lymphocytes able to recognize the host HLA antigens. The activity of these host-reactive T cells is suppressed in vivo, since no graft-vs. -host disease is observed in these human chimeras. Here it is shown that the CD4+ host-reactive T cell clones isolated from a SCID patient transplanted with fetal liver stem cells produce unusually high quantities of interleukin 10 (IL-10) and very low amounts of IL-2 after antigen-specific stimulation in vitro. The specific proliferative responses of the host-reactive T cell clones were considerably enhanced in the presence of neutralizing concentrations of an anti-IL-10 monoclonal antibody, suggesting that high levels of endogenous IL-10 suppress the activity of these cells. These in vitro data correlate with observations made in vivo. Semi-quantitative polymerase chain reaction analysis carried out on freshly isolated peripheral blood mononuclear cells (PBMC) of the patient indicated that the levels of IL-10 messenger RNA (mRNA) expression were strongly enhanced, whereas IL-2 mRNA expression was much lower than that in PBMC of healthy donors. In vivo IL-10 mRNA expression was not only high in the T cells, but also in the non-T cell fraction, indicating that host cells also contributed to the high levels of IL-10 in vivo. Patient-derived monocytes were found to be major IL-10 producers. Although no circulating IL-10 could be detected, freshly isolated monocytes of the patient showed a reduced expression of class II HLA antigens. However, their capacity to stimulate T cells of normal donors in primary mixed lymphocyte cultures was within the normal range. Interestingly, similar high in vivo IL-10 mRNA expressions in the T and non-T cell compartment were also observed in three SCID patients transplanted with fetal liver stem cells and in four SCID patients transplanted with T cell-depleted haploidentical bone marrow stem cells. Taken together, these data indicate that high endogenous IL-10 production is a general phenomenon in SCID patients in whom allogenic stem cell transplantation results in immunologic reconstitution and induction of tolerance. Both donor T cells and host accessory cells contribute to these high levels of IL-10, which would suppress the activity of host-reactive T cell in vivo.

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The Role of Interleukin-10 (IL-10) in IL-15–Mediated T-Cell Responses

Blood ◽

10.1182/blood.v90.11.4513 ◽

1997 ◽

Vol 90 (11) ◽

pp. 4513-4521 ◽

Cited By ~ 24

Author(s):

Dieter Körholz ◽

Ursula Banning ◽

Halvard Bönig ◽

Markus Grewe ◽

Marion Schneider ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Interleukin 10 ◽

T Cell Proliferation ◽

Cell Production ◽

Cd25 Expression ◽

Tnf Α ◽

Ifn Γ

Abstract Interleukin-15 (IL-15) is a potent T-cell stimulating factor, which has recently been used for pre-clinical in vivo immunotherapy. Here, the IL-15 effect on CD3-stimulated peripheral human T cells was investigated. IL-15 induced a significant T-cell proliferation and upregulated CD25 expression. IL-15 significantly enhanced T-cell production of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-10. Between 10- and 100-fold greater concentrations of IL-15 were necessary to reach a biological effect equivalent to that of IL-2. Blockade of IL-2 binding to the high-affinity IL-2 receptor did not affect the IL-15 effects, suggesting that IL-15 did not act by inducing endogenous IL-2. Exogenously administered IL-10 significantly reduced the IL-15 and IL-2–mediated IFN-γ and TNF-α production, whereas T-cell proliferation and CD25 expression were not affected. The inhibitory effects of exogenously administered IL-10 on T-cell cytokine production appeared indirect, and are likely secondary to decreased IL-12 production by accessory cells. Inhibition of endogenous IL-10 binding to the IL-10 receptor significantly increased IFN-γ and TNF-α release from T cells. These data suggest that endogenous IL-10 can regulate activated T-cell production of IFN-γ and TNF-α via a paracrine negative feedback loop. The observations of this study could be of relevance for the therapeutic use of IL-15 in vivo.

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Cytokine profile and T cell adhesiveness to endothelial selectins: in vivo induction by a myasthenogenic T cell epitope and immunomodulation by a dual altered peptide ligand

International Immunology ◽

10.1093/intimm/12.12.1651 ◽

2000 ◽

Vol 12 (12) ◽

pp. 1651-1658 ◽

Cited By ~ 10

Author(s):

Anat Faber-Elmann ◽

Valentin Grabovsky ◽

Molly Dayan ◽

Michael Sela ◽

Ronen Alon ◽

...

Keyword(s):

T Cell ◽

Cell Epitope ◽

Cytokine Profile ◽

Peptide Ligand ◽

Altered Peptide Ligand ◽

T Cell Epitope ◽

In Vivo Induction

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Blockade of Costimulation Prevents Infection-Induced Immunopathology in Interleukin-10-Deficient Mice

Infection and Immunity ◽

10.1128/iai.68.5.2837-2844.2000 ◽

2000 ◽

Vol 68 (5) ◽

pp. 2837-2844 ◽

Cited By ~ 25

Author(s):

Eric N. Villegas ◽

Ulrike Wille ◽

Linden Craig ◽

Peter S. Linsley ◽

Donna M. Rennick ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Serum Levels ◽

Cd40 Ligand ◽

Interleukin 10 ◽

Cell Mediated Immunity ◽

Ifn Γ ◽

Oxide Synthase

ABSTRACT Interleukin-10 (IL-10) is associated with inhibition of cell-mediated immunity and downregulation of the expression of costimulatory molecules required for T-cell activation. When IL-10-deficient (IL-10KO) mice are infected with Toxoplasma gondii, they succumb to a T-cell-mediated shock-like reaction characterized by the overproduction of IL-12 and gamma interferon (IFN-γ) associated with widespread necrosis of the liver. Since costimulation is critical for T-cell activation, we investigated the role of the CD28-B7 and CD40-CD40 ligand (CD40L) interactions in this infection-induced immunopathology. Our studies show that infection of mice with T. gondii resulted in increased expression of B7 and CD40 that was similar in wild-type and IL-10KO mice. In vivo blockade of the CD28-B7 or CD40-CD40L interactions following infection of IL-10KO mice with T. gondii did not affect serum levels of IFN-γ or IL-12, nor did it prevent death in these mice. However, when both pathways were blocked, the IL-10KO mice survived the acute phase of infection and had reduced serum levels of IFN-γ and alanine transaminase as well as decreased expression of inducible nitric oxide synthase in the liver and spleen. Analysis of parasite-specific recall responses from infected IL-10KO mice revealed that blockade of the CD40-CD40L interaction had minimal effects on cytokine production, whereas blockade of the CD28-B7 interaction resulted in decreased production of IFN-γ but not IL-12. Further reduction of IFN-γ production was observed when both costimulatory pathways were blocked. Together, these results demonstrate that the CD28-B7 and CD40-CD40L interactions are involved in the development of infection-induced immunopathology in the absence of IL-10.

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Th1 versus Th2 cytokine profile determines the modulation of in vitro T cell-independent type 2 responses by IL-4

International Immunology ◽

10.1093/intimm/12.9.1337 ◽

2000 ◽

Vol 12 (9) ◽

pp. 1337-1345 ◽

Cited By ~ 9

Author(s):

Quirijn Vos ◽

Clifford M. Snapper ◽

James J. Mond

Keyword(s):

T Cell ◽

Cytokine Profile ◽

Th2 Cytokine

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TH2 CYTOKINE PROFILE MODULATION BY INTERLEUKIN-10 ADMINISTRATION AUGMENTS GRAFT ARTERIAL DISEASE IN MURINE HEART ALLOGRAFTS.

Transplantation Journal ◽

10.1097/00007890-199904150-01001 ◽

1999 ◽

Vol 67 (7) ◽

pp. S251

Author(s):

Y. Furukawa ◽

G. Becker ◽

J. L. Stinn ◽

P. Libby ◽

R. N. Mitchell

Keyword(s):

Arterial Disease ◽

Interleukin 10 ◽

Cytokine Profile ◽

Th2 Cytokine

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Dietary Antigen-Specific T-Cell Responses: Switch from an Interleukin-10-Dominated Response in Normal Mice to a T-Helper 1 Cytokine Profile in Galphai2-Deficient Mice prior to Colitis

Scandinavian Journal of Immunology ◽

10.1111/j.0300-9475.2005.01535.x ◽

2005 ◽

Vol 61 (1) ◽

pp. 29-35 ◽

Cited By ~ 9

Author(s):

M. Bjursten ◽

E. Hultgren Hornquist

Keyword(s):

T Cell ◽

T Cell Responses ◽

Interleukin 10 ◽

Cytokine Profile ◽

T Helper ◽

T Helper 1 ◽

Cell Responses ◽

Dietary Antigen ◽

Deficient Mice

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In-Vivo Generation of Antigen-Specific Tregs with AAV8 Suppresses Collagen-Induced Arthritis in DBA1 Mice through IL-10 Production

10.21203/rs.3.rs-558817/v1 ◽

2021 ◽

Author(s):

Matthew Wade ◽

Hugues Fausther-Bovendo ◽

Marc-Antoine De La Vega ◽

Gary Kobinger

Keyword(s):

T Cell ◽

Autoimmune Diseases ◽

Immune Suppression ◽

Interleukin 10 ◽

T Cell Epitopes ◽

Collagen Induced Arthritis ◽

Adeno Associated Virus ◽

Virus Serotype ◽

Collagen Ii

Abstract Available therapeutics for autoimmune disorders focused on mitigating symptoms, rather than treating the cause of the disorder. A novel approach using adeno-associated virus (AAV) could restore tolerance to the autoimmune targets and provide a permanent treatment for autoimmune diseases. Here, we evaluated the ability of collagen II T-cell epitopes packaged in adeno-associated virus serotype 8 (AAV-8) vectors to reduce pathogenic cellular and humoral responses against collagen and to mitigate the disease in the collagen-induced arthritis mouse model. The cytokines and immune cells involved in the immune suppression were also investigated. Mice treated with AAV-8 containing collagen II T-cell epitopes demonstrated a significant reduction in the arthritis symptoms, pathogenic collagen specific antibody and T cell responses. The AAV-8 mediated immune suppression was mediated by increased interleukin-10 expression and regulatory T cells expansion. Altogether, this study strengthens the notion that AAV vectors are promising candidates for the treatment of autoimmune diseases.

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Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽

10.1182/blood-2004-01-0365 ◽

2004 ◽

Vol 104 (10) ◽

pp. 3249-3256 ◽

Cited By ~ 303

Author(s):

Laurence Weiss ◽

Vladimira Donkova-Petrini ◽

Laure Caccavelli ◽

Michèle Balbo ◽

Cédric Carbonneil ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Highly Active Antiretroviral Therapy ◽

Cd4 T Cells ◽

Transforming Growth Factor ◽

Cell Subset ◽

Transforming Growth Factor Β ◽

Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

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