Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 21
Filter
Add more filters










Publication year range
1.
Proc Natl Acad Sci U S A ; 121(13): e2306763121, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38498711

ABSTRACT

Lactate-proton symporter monocarboxylate transporter 1 (MCT1) facilitates lactic acid export from T cells. Here, we report that MCT1 is mandatory for the development of virus-specific CD8+ T cell memory. MCT1-deficient T cells were exposed to acute pneumovirus (pneumonia virus of mice, PVM) or persistent γ-herpesvirus (Murid herpesvirus 4, MuHV-4) infection. MCT1 was required for the expansion of virus-specific CD8+ T cells and the control of virus replication in the acute phase of infection. This situation prevented the subsequent development of virus-specific T cell memory, a necessary step in containing virus reactivation during γ-herpesvirus latency. Instead, persistent active infection drove virus-specific CD8+ T cells toward functional exhaustion, a phenotype typically seen in chronic viral infections. Mechanistically, MCT1 deficiency sequentially impaired lactic acid efflux from activated CD8+ T cells, caused an intracellular acidification inhibiting glycolysis, disrupted nucleotide synthesis in the upstream pentose phosphate pathway, and halted cell proliferation which, ultimately, promoted functional CD8+ T cell exhaustion instead of memory development. Taken together, our data demonstrate that MCT1 expression is mandatory for inducing T cell memory and controlling viral infection by CD8+ T cells.


Subject(s)
CD8-Positive T-Lymphocytes , Symporters , Animals , Mice , CD8-Positive T-Lymphocytes/metabolism , Lactic Acid/metabolism , Biological Transport , Symporters/genetics , Symporters/metabolism
2.
Int J Mol Sci ; 22(13)2021 Jun 24.
Article in English | MEDLINE | ID: mdl-34202553

ABSTRACT

The cells of the immune system, particularly the T lymphocytes, have two main features that distinguish them from the cells of other tissues. They proliferate after activation and have the ability to move in tissues and organs. These characteristics compel them to develop metabolic plasticity in order to fulfil their immune function. This review focuses on the different known mechanisms that allow T cells to adapt their metabolism to the real-life circumstances they operate in, whether it is to exit quiescence, to differentiate into effector cells, or to participate in immune memory formation. Some of the metabolic adaptations to environmental variations that T cells are likely to undergo in their immune monitoring function are also discussed.


Subject(s)
Energy Metabolism , T-Lymphocytes/metabolism , Adaptive Immunity , Animals , Cell Differentiation/immunology , Humans , Immunologic Memory , Lymphocyte Activation/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
3.
Elife ; 72018 06 18.
Article in English | MEDLINE | ID: mdl-29911570

ABSTRACT

Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronic T cells appeared to rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to produce ATP for IFNγ synthesis. Check-point blockade, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1-mediated inhibition appears essential for limiting oxidative metabolism linked to effector function in chronic T cells, thereby promoting survival and functional fitness.


Subject(s)
B7-H1 Antigen/genetics , Cell Lineage/immunology , Interferon-gamma/genetics , Programmed Cell Death 1 Receptor/genetics , T-Lymphocytes/immunology , Adenosine Triphosphate/antagonists & inhibitors , Adenosine Triphosphate/biosynthesis , Animals , Antibodies, Monoclonal/pharmacology , Antimetabolites, Antineoplastic/pharmacology , B7-H1 Antigen/immunology , Cell Lineage/drug effects , Cell Lineage/genetics , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , DNA-Binding Proteins/immunology , Diazooxonorleucine/pharmacology , Epoxy Compounds/pharmacology , Gene Expression Profiling , Gene Expression Regulation , Glycolysis/drug effects , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/immunology , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Interleukin Receptor Common gamma Subunit/immunology , Lymphocyte Activation , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Oligomycins/pharmacology , Oxidative Phosphorylation/drug effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Signal Transduction , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/transplantation , Transplantation, Homologous
4.
Eur J Immunol ; 46(7): 1574-82, 2016 07.
Article in English | MEDLINE | ID: mdl-27271222

ABSTRACT

T-cell metabolism is central to the shaping of a successful immune response. However, there are pathological situations where T cells are rendered dysfunctional and incapable of eliminating infected or transformed cells. Here, we review the current knowledge on T-cell metabolism and how persistent antigenic stimulation, in the form of cancer and chronic viral infection, modifies both metabolic and functional pathways in T cells.


Subject(s)
Cellular Reprogramming/immunology , Energy Metabolism/immunology , Lymphocyte Activation/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Adaptation, Biological/genetics , Adaptation, Biological/immunology , Animals , Antigens/immunology , Cellular Reprogramming/genetics , Energy Metabolism/genetics , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunologic Memory , Lymphocyte Activation/genetics , Neoplasms/immunology , Neoplasms/metabolism , Signal Transduction , T-Lymphocyte Subsets/cytology , Virus Diseases/immunology , Virus Diseases/metabolism
5.
PLoS One ; 10(12): e0145237, 2015.
Article in English | MEDLINE | ID: mdl-26670809

ABSTRACT

We previously identified heme oxygenase 1 (HO-1) as a specific target of miR-155, and inhibition of HO-1 activity restored the capacity of miR-155-/- CD4+ T cells to promote antigen-driven inflammation after adoptive transfer in antigen-expressing recipients. Protoporphyrins are molecules recognized for their modulatory effect on HO-1 expression and function. In the present study, we investigated the effect of protoporphyrin treatment on the development of autoimmunity in miR-155-deficient mice. MiR-155-mediated control of HO-1 expression in promoting T cell-driven chronic autoimmunity was confirmed since HO-1 inhibition restored susceptibility to experimental autoimmune encephalomyelitis (EAE) in miR-155-deficient mice. The increased severity of the disease was accompanied by an enhanced T cell infiltration into the brain. Taken together, these results underline the importance of miR-155-mediated control of HO-1 expression in regulating the function of chronically-stimulated T cells in EAE.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/genetics , MicroRNAs/metabolism , Protoporphyrins/therapeutic use , Animals , Brain/drug effects , Brain/pathology , Disease Susceptibility , Encephalomyelitis, Autoimmune, Experimental/pathology , Heme Oxygenase-1/antagonists & inhibitors , Heme Oxygenase-1/metabolism , Lymph Nodes/drug effects , Lymph Nodes/immunology , Mice, Inbred C57BL , MicroRNAs/genetics , Protoporphyrins/pharmacology , Spleen/drug effects , Spleen/immunology , Th1 Cells/drug effects , Th17 Cells/drug effects
6.
Eur J Immunol ; 45(3): 829-42, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25641586

ABSTRACT

T cells chronically stimulated by a persistent antigen often become dysfunctional and lose effector functions and proliferative capacity. To identify the importance of micro-RNA-155 (miR-155) in this phenomenon, we analyzed mouse miR-155-deficient CD4(+) T cells in a model where the chronic exposure to a systemic antigen led to T-cell functional unresponsiveness. We found that miR-155 was required for restoring function of T cells after programmed death receptor 1 blockade. Heme oxygenase 1 (HO-1) was identified as a specific target of miR-155 and inhibition of HO-1 activity restored the expansion and tissue migration capacity of miR-155(-/-) CD4(+) T cells. Moreover, miR-155-mediated control of HO-1 expression in CD4(+) T cells was shown to sustain in vivo antigen-specific expansion and IL-2 production. Thus, our data identify HO-1 regulation as a mechanism by which miR-155 promotes T-cell-driven inflammation.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Gene Expression Regulation, Enzymologic/immunology , Heme Oxygenase-1/immunology , Immune Tolerance , Membrane Proteins/immunology , MicroRNAs/immunology , Animals , Gene Expression Regulation, Enzymologic/genetics , Heme Oxygenase-1/genetics , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Interleukin-2/genetics , Interleukin-2/immunology , Membrane Proteins/genetics , Mice , Mice, Knockout , MicroRNAs/genetics , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology
7.
Immun Inflamm Dis ; 3(4): 431-44, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26734465

ABSTRACT

The protein S100A4 is best known for its significant role in promoting motility and invasive capacity of cancer cells. Since S100A4 expression has been reported also in T cells, we analyzed its potential role in T cell motility and inflammation. Using S100a4(+/Gfp) mice, we show here that S100A4 is exclusively expressed by memory T cells of CD4(+) or CD8(+) subpopulations, predominantly of the effector memory T cell subtype. However, the protein was not required for in vitro memory T cell migration toward gradients of the inflammatory chemokine CXCL10. Moreover, T cell memory response was normal in S100A4-deficient mice and lack of S100a4 gene expression did not induce any defect in promoting the development of protective immunity or inflammatory reactions leading to autoimmunity. Taken together, our results demonstrate that S100A4 activity is dispensable for T cell motility/migration and inflammatory potential.

9.
Int Immunol ; 26(7): 407-15, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24648472

ABSTRACT

MiR-155 (-/-) mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), while Pdcd1 (-/-) mice develop a more severe form of the disease. To determine the conflicting roles of these two molecules in the disease, we generated miR-155 (-/-) Pdcd1 (-/-) double knockout (DKO) mice. We found that ablation of programmed cell death protein 1 (PD-1) expression in miR-155-deficient mice restored the susceptibility to EAE. The increased severity of the disease in DKO mice was accompanied by an enhanced T-cell infiltration into the brain as well as an increased production of pro-inflammatory cytokines IFN-γ and IL-17. Furthermore, the major contribution of the DKO to EAE was T-cell intrinsic since adoptive transfer of CD4(+) T cells from DKO donors promoted the disease in lymphopenic recipients. These results define PD-1 deficiency in miR-155 (-/-) mice as a promoting factor of autoimmune inflammation by increasing antigen-driven T-cell expansion and infiltration.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/genetics , MicroRNAs/immunology , Programmed Cell Death 1 Receptor/immunology , Adoptive Transfer , Animals , Brain/immunology , Brain/pathology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/transplantation , Cell Movement , Disease Susceptibility , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Gene Expression Regulation , Interferon-gamma/biosynthesis , Interferon-gamma/metabolism , Interleukin-17/biosynthesis , Interleukin-17/metabolism , Mice , Mice, Knockout , MicroRNAs/genetics , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/pathogenicity , Myelin-Oligodendrocyte Glycoprotein , Peptide Fragments , Programmed Cell Death 1 Receptor/deficiency , Programmed Cell Death 1 Receptor/genetics , Severity of Illness Index , Signal Transduction , Spleen/immunology , Spleen/pathology
10.
Infect Immun ; 79(5): 2043-50, 2011 May.
Article in English | MEDLINE | ID: mdl-21383053

ABSTRACT

We investigated the early innate immune responses induced in human intestinal epithelial cells (IEC) by the three defined Toxoplasma gondii genotype strains. Transcriptome analysis revealed that among differentially expressed genes, ß-defensins distinguished the most IEC infected by fast- or slow-replicating T. gondii genotypes. Although ß-defensin 1 and 3 genes were not expressed in host cells at early time points postinfection, the slow-replicating type II and III parasites induced high levels of ß-defensin 2 gene expression. Notably, no ß-defensin 2 gene expression occurred early after infection with the fast-replicating type I parasite. However, activation of this gene in IEC by poly(I:C) treatment prior to infection substantially decreased parasite viability, and pretreatment of parasites with synthetic ß-defensin 2 significantly reduced their infectivity of IEC. These findings strongly support the modulation of early ß-defensin 2 expression as a mechanism used by type I T. gondii parasites to mediate immune evasion.


Subject(s)
Immune Evasion/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Toxoplasmosis/immunology , beta-Defensins/biosynthesis , Gene Expression , Gene Expression Profiling , Humans , Immunity, Mucosal/immunology , Intestinal Mucosa/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Toxoplasma/growth & development , Toxoplasma/immunology , Toxoplasma/pathogenicity , Toxoplasmosis/metabolism , beta-Defensins/immunology
11.
Methods Mol Biol ; 677: 419-30, 2011.
Article in English | MEDLINE | ID: mdl-20941624

ABSTRACT

T-cell activation depends upon two types of signals: a T-cell-receptor-mediated antigen-specific signal and several non-antigen-specific ones provided by the engagement of costimulatory and/or inhibitory T-cell surface molecules. In clinical transplantation, T-cell costimulatory/inhibitory molecules are involved in determining cytokine production, vascular endothelial cell damage, and induction of transplant rejection. Several of the latest new immunotherapeutic strategies being currently developed to control graft rejection aim at inhibiting alloreactive T-cell function by regulating activating and costimulatory/inhibitory signals to T cells. This article describes the recent development and potential application of these therapies in experimental and pre-clinical transplantation.


Subject(s)
Cell- and Tissue-Based Therapy/trends , Graft Rejection/immunology , Receptors, Cell Surface/metabolism , T-Lymphocytes/immunology , Cells, Cultured , Humans , Immune Tolerance/immunology , Organ Transplantation , Receptors, Antigen, T-Cell/immunology , Signal Transduction/immunology , T-Lymphocytes/physiology , Transplantation Tolerance
12.
J Immunol ; 184(12): 6790-8, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20488796

ABSTRACT

CD3-negative NK cells are granular lymphocytes capable of producing inflammatory cytokines and killing malignant, infected, or stressed cells. We have recently observed a new role for NK cells in the control of the proliferation of CD4 T cells under persistent antigenic stimulation. Monoclonal anti-male CD4 T cells transferred into Rag2-/- male recipients did not expand or were rapidly eliminated. Remarkably, T cells transferred into NK cell-deficient Rag2-/- Il-2Rgammac-/- male hosts expanded extensively and mediated tissue lesions usually observed in chronic graft-versus-host disease (GVHD). T cell failure to proliferate and to induce chronic GVHD was the result of NK cell activity, because depletion of the recipient's NK1.1+ cells by Ab treatment induced T cell expansion and chronic GVHD. T cells under chronic Ag stimulation upregulated ligands of the activating receptor NKG2D, and regulatory activity of NK cells was inhibited by the injection of Abs directed to NKG2D. On the contrary, blocking NKG2A inhibitory receptors did not increase NK cell regulatory activity. Finally, we show that NK regulation of T cell expansion did not involve perforin-mediated lytic activity of NK cells, but depended on T cell surface expression of a functional Fas molecule. These results highlight the potential role played by NK cells in controlling the Ag-specific CD4+ T cells responsible for chronic GVHD.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Graft vs Host Disease/immunology , Killer Cells, Natural/immunology , Lymphocyte Activation/immunology , Adoptive Transfer , Animals , Cell Proliferation , Cell Separation , Female , Flow Cytometry , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NK Cell Lectin-Like Receptor Subfamily K/immunology , Reverse Transcriptase Polymerase Chain Reaction
13.
J Immunol ; 183(7): 4284-91, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19734216

ABSTRACT

In bone marrow-transplanted patients, chronic graft-versus-host disease is a complication that results from the persistent stimulation of recipient minor histocompatibility Ag (mHA)-specific T cells contained within the graft. In this study, we developed a mouse model where persistent stimulation of donor T cells by recipient's mHA led to multiorgan T cell infiltration. Exposure to systemic mHA, however, deeply modified T cell function and chronically stimulated T cells developed a long-lasting state of unresponsiveness, or immune adaptation, characterized by their inability to mediate organ immune damages in vivo. However, analysis of the gene expression profile of adapted CD4+ T cells revealed the specific coexpression of genes known to promote differentiation and function of Th1 effector cells as well as genes coding for proteins that control T cell activity, such as cell surface-negative costimulatory molecules and regulatory cytokines. Strikingly, blockade of negative costimulation abolished T cell adaptation and stimulated strong IFN-gamma production and severe multiorgan wasting disease. Negative costimulation was also shown to control lethal LPS-induced toxic shock in mice with adapted T cells, as well as the capacity of adapted T cells to reject skin graft. Our results demonstrate that negative costimulation is the molecular mechanism used by CD4+ T cells to adapt their activity in response to persistent antigenic stimulation. The effector function of CD4+ T cells that have adapted to chronic Ag presentation can be activated by stimuli strong enough to overcome regulatory signals delivered to the T cells by negative costimulation.


Subject(s)
Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/immunology , Immune Tolerance , Amino Acid Sequence , Animals , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/transplantation , Cells, Cultured , Female , H-Y Antigen/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Minor Histocompatibility Antigens/immunology , Molecular Sequence Data , Skin Transplantation/immunology
14.
J Immunol ; 179(2): 910-7, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17617582

ABSTRACT

Mice made unresponsive by repeated injection of staphylococcal enterotoxin B (SEB) contained SEB-specific CD25(+)CD4(+)TCRBV8(+) T cells that were able to transfer their state of unresponsiveness to primary-stimulated T cells. About one-half of these cells stably up-regulated the expression of CD152. We undertook the present study to determine whether CD152(high) cells seen in this system were T regulatory cells responsible for suppression or whether they represented SEB-activated CD4(+) T effector cells. Our results show that, among SEB-specific TCRBV8(+) T cells isolated from unresponsive mice, all CD152(high)CD25(+)CD4(+) T cells expressed Foxp3, the NF required for differentiation and function of natural T regulatory cells. Moreover, suppression by CD25(+)CD4(+)TCRBV8(+) T cells was fully inhibited by anti-CD152 Abs. Following stimulation by soluble CD152-Ig, dendritic cells (DC) isolated from unresponsive mice strongly increased the expression and the function of indoleamine-2,3-dioxygenase (IDO), the enzyme responsible for the catabolism of tryptophan. This capacity to activate IDO was independent of IFN-gamma production by DC because CD152-Ig stimulation of DC isolated from SEB-treated IFN-gamma-deficient animals activated IDO expression and function. Finally, adding 1-methyl-tryptophan, an inhibitor of tryptophan catabolism, increased substantially the capacity of DC from unresponsive animals to stimulate primary T cell response toward SEB. Thus, we conclude that IFN-gamma-independent CD152-mediated activation of tryptophan catabolism by Foxp3(+)CD25(+) T regulatory cells provides DC with immune regulatory activity in mice unresponsive to SEB.


Subject(s)
Antigens, CD/biosynthesis , Antigens, Differentiation/biosynthesis , Dendritic Cells/immunology , Enterotoxins/immunology , Immune Tolerance/physiology , T-Lymphocytes, Regulatory/immunology , Tryptophan/metabolism , Animals , Blotting, Western , CTLA-4 Antigen , Chromatography, High Pressure Liquid , Enzyme Activation , Female , Flow Cytometry , Forkhead Transcription Factors/biosynthesis , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Interferon-gamma/immunology , Interleukin-2 Receptor alpha Subunit/immunology , Mice , Mice, Inbred BALB C , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/metabolism
15.
Transplantation ; 82(4): 582-91, 2006 Aug 27.
Article in English | MEDLINE | ID: mdl-16958183

ABSTRACT

BACKGROUND: Whereas the participation of alloreactive T cells sensitized by indirect allorecognition in graft rejection is well documented, the nature of recipient antigen presenting cells recognized by indirect pathway CD4+ T cells within the graft has yet to be identified. The purpose of this study was to determine the role played by graft endothelium replacement in the immune recognition of cardiac allografts rejected by indirect pathway CD4+ T cells. METHODS: Transgenic RAG2-/- mice expressing I-Ab-restricted male antigen H-Y-specific TcR were studied for their capacity to reject H-2k male cardiac allografts. Chronic vascular rejection in this model was due to the indirect recognition of H-Y antigen shed from H-2k male allograft and presented by the recipient's own I-Ab APC to transgenic T cells. RESULTS: Immunohistochemical analysis of rejected grafts revealed the presence of numerous microvascular endothelial cells (EC) that expressed recipient's I-Ab MHC class II molecules. This observation suggested that graft endothelium replacement by I-Ab-positive cells of recipient origin could stimulate the rejection of male H-2k graft by I-Ab-restricted H-Y-specific T cells. To investigate further this possibility, hearts from H-2b-into-H-2k irradiation bone marrow (BM) chimera were transplanted in transgenic recipients. A direct correlation was observed between the presence of I-Ab-positive EC within myocardial microvessels and the induction of acute rejection of chimeric H-2k male cardiac allografts transplanted in transgenic recipients. CONCLUSIONS: We conclude that graft endothelium replacement by recipient-type cells is required for the rejection of cardiac allograft mediated by indirect pathway alloreactive CD4+ T cells.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Endothelium, Vascular/physiology , Graft Rejection/immunology , Heart Transplantation/immunology , Amino Acid Sequence , Animals , Female , Histocompatibility Antigens Class II/analysis , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , Molecular Sequence Data , Receptors, Antigen, T-Cell/physiology , Transplantation, Homologous
16.
Transplantation ; 81(5): 726-35, 2006 Mar 15.
Article in English | MEDLINE | ID: mdl-16534475

ABSTRACT

BACKGROUND: Whereas the participation of alloreactive T cells sensitized by indirect allorecognition in graft rejection is well documented, the nature of recipient antigen presenting cells recognized by indirect pathway CD4(+) T cells within the graft has yet to be identified. The purpose of this study was to determine the role played by graft endothelium replacement in the immune recognition of cardiac allografts rejected by indirect pathway CD4(+) T cells. METHODS: Transgenic RAG2(-/-) mice expressing I-A(b)-restricted male antigen H-Y-specific TcR were studied for their capacity to reject H-2(k) male cardiac allografts. Chronic vascular rejection in this model was due to the indirect recognition of H-Y antigen shed from H-2(k) male allograft and presented by the recipient's own I-A(b) APC to transgenic T cells. RESULTS: Immunohistochemical analysis of rejected grafts revealed the presence of numerous microvascular endothelial cells (EC) that expressed recipient's I-A MHC class II molecules. This observation suggested that graft endothelium replacement by I-A(b)-positive cells of recipient origin could stimulate the rejection of male H-2(k) graft by I-A(b)--restricted H-Y--specific T cells. To investigate further this possibility, hearts from H-2(b)--into--H-2(k) irradiation bone marrow (BM) chimera were transplanted in transgenic recipients. A direct correlation was observed between the presence of I-A(b)-positive EC within myocardial microvessels and the induction of acute rejection of chimeric H-2(k) male cardiac allografts transplanted in transgenic recipients. CONCLUSIONS: We conclude that graft endothelium replacement by recipient-type cells is required for the rejection of cardiac allograft mediated by indirect pathway alloreactive CD4(+) T cells.


Subject(s)
Antigen-Presenting Cells/immunology , CD4-Positive T-Lymphocytes/immunology , Endothelium, Vascular/immunology , Graft Rejection/immunology , Heart Transplantation/immunology , Histocompatibility Antigens Class II/analysis , Animals , Blood Vessels/immunology , Blood Vessels/pathology , DNA-Binding Proteins/genetics , Endothelial Cells/immunology , Endothelial Cells/pathology , Endothelium, Vascular/pathology , Female , H-2 Antigens/analysis , Male , Mice , Mice, Transgenic , Receptors, Antigen/genetics , Transplants
17.
Eur Cytokine Netw ; 16(3): 233-9, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16266865

ABSTRACT

We recently showed that interleukin-9 (IL-9), a Th2 cytokine, promotes IL-5-mediated rejection of allografts in mice. This observation led us to investigate the functional link between IL-9 and IL-5 production during alloreactive T cell responses in vitro and in vivo. Firstly, we found that IL-9 was produced by alloreactive Th2 cells, and IL-9 mRNA was detected in skin allograft during Th2-type rejection. We then established that IL-5 production was impaired in alloreactive Th2 cells isolated from IL-9-deficient mice and that optimal IL-5 production after allogeneic stimulation requires a functional IL-9 receptor (IL-9R) on the responding cells. Finally, the production of IL-5 by anti-CD3-stimulated CD4+ T cells was abolished by neutralization of IL-9. Despite the fact that IL-9 promotes IL-5 production by alloreactive T cells, IL-9-deficient recipients of skin allografts still developed eosinophilic graft infiltrates and neither IL-9 nor IL-9R deficiency modified Th2-type allograft rejection.


Subject(s)
Graft Rejection/immunology , Interleukin-5/biosynthesis , Interleukin-9/physiology , Th2 Cells/immunology , Animals , Cells, Cultured , Eosinophils/immunology , Interleukin-9/biosynthesis , Interleukin-9/pharmacology , Isoantigens/immunology , Mice , Mice, Transgenic , Receptors, Interleukin/metabolism , Receptors, Interleukin-9 , Skin Transplantation/immunology , Spleen/cytology , Spleen/immunology , Th2 Cells/drug effects
18.
Transplantation ; 79(6): 648-54, 2005 Mar 27.
Article in English | MEDLINE | ID: mdl-15785370

ABSTRACT

BACKGROUND: Allografts are occasionally accepted in the absence of immunosuppression. Because naturally occurring CD4(+)CD25(+) regulatory T cells (natural CD25(+) Treg cells) have been shown to inhibit allograft rejection, we investigated their influence on the outcome of allografts in nonimmunosuppressed mouse recipients. METHODS: We compared survival times of male CBA/Ca skin grafts in female CBA/Ca recipients expressing a transgenic anti-HY T-cell receptor on a RAG-1(+/+) (A1[M]RAG+) or a RAG-1(-/-) (A1[M]RAG-) background. Depletion of natural CD25(+) Treg cells in A1[M]RAG+ mice was achieved by in vivo administration of the PC61 monoclonal antibody. The influence of natural CD25(+) Treg cells on the fate of major histocompatibility complex class II-mismatched (C57BL/6X bm12)F1 skin or bm12 heart transplants in C57BL/6 recipients was also assessed. Finally, we investigated the impact of natural CD25(+) Treg cells on the production of T-helper (Th)1 and Th2 cytokines in mixed lymphocyte cultures between C57BL/6 CD4(+) CD25(-) T cells as responders and bm12 or (C57BL/6X bm12)F1 antigen-presenting cells as stimulators. RESULTS: Male allografts were spontaneously accepted by female A1(M)RAG+ mice but readily rejected by female A1(M)RAG+ mice depleted of natural CD25(+) Treg cells by pretreatment with the PC61 monoclonal antibody. Depletion of CD25(+) Treg cells also enhanced eosinophil-determined rejection of (C57BL/6X bm12)F1 skin grafts or bm12 cardiac grafts in C57BL/6 recipients. Finally, natural CD25(+) Treg cells inhibited the production of interleukin (IL)-2, interferon-gamma, IL-5, and IL-13 in mixed lymphocyte culture in a dose-dependent manner. CONCLUSION: Natural CD25(+) Treg cells control Th1- and Th2-type allohelper T-cell responses and thereby influence the fate of allografts in nonimmunosuppressed recipients.


Subject(s)
Graft Survival/immunology , Receptors, Interleukin-2/immunology , T-Lymphocytes/immunology , Animals , Cytokines/immunology , Cytokines/metabolism , Female , Graft Rejection/immunology , Heart Transplantation/immunology , Heart Transplantation/pathology , Immunosuppression Therapy , Lymphocyte Culture Test, Mixed , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Rats , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Interleukin-2/metabolism , Skin Transplantation/immunology , Skin Transplantation/pathology , T-Lymphocytes/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Transplantation , Transplantation, Homologous/immunology
19.
J Immunol ; 171(7): 3475-84, 2003 Oct 01.
Article in English | MEDLINE | ID: mdl-14500643

ABSTRACT

The repeated injection of low doses of bacterial superantigens (SAg) is known to induce specific T cell unresponsiveness. We show in this study that the spleen of BALB/c mice receiving chronically, staphylococcal enterotoxin B (SEB) contains SEB-specific CD4(+) TCRBV8(+) T cells exerting an immune regulatory function on SEB-specific primary T cell responses. Suppression affects IL-2 and IFN-gamma secretion as well as proliferation of T cells. However, the suppressor cells differ from the natural CD4(+) T regulatory cells, described recently in human and mouse, because they do not express cell surface CD25. They are CD152 (CTLA-4)-negative and their regulatory activity is not associated with expression of the NF Foxp3. By contrast, after repeated SEB injection, CD4(+)CD25(+) splenocytes were heterogenous and contained both effector as well as regulatory cells. In vivo, CD4(+)CD25(-) T regulatory cells prevented SEB-induced death independently of CD4(+)CD25(+) T cells. Nevertheless, SEB-induced tolerance could not be achieved in thymectomized CD25(+) cell-depleted mice because repeated injection of SEB did not avert lethal toxic shock in these animals. Collectively, these data demonstrate that, whereas CD4(+)CD25(+) T regulatory cells are required for the induction of SAg-induced tolerance, CD4(+)CD25(-) T cells exert their regulatory activity at the maintenance stage of SAg-specific unresponsiveness.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Clonal Anergy/immunology , Enterotoxins/administration & dosage , Receptors, Interleukin-2/biosynthesis , Superantigens/administration & dosage , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Antigens, CD , Antigens, Differentiation/biosynthesis , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/microbiology , CTLA-4 Antigen , Cell Movement/immunology , Cell Separation , Dose-Response Relationship, Immunologic , Down-Regulation/immunology , Drug Administration Schedule , Enterotoxins/immunology , Epitopes, T-Lymphocyte/administration & dosage , Epitopes, T-Lymphocyte/immunology , Female , Injections, Intraperitoneal , Lymphocyte Depletion , Mice , Mice, Inbred BALB C , Spleen/cytology , Spleen/immunology , Staphylococcus aureus/immunology , Superantigens/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/microbiology , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/microbiology , Thymus Gland/cytology , Thymus Gland/immunology
20.
Transplantation ; 76(3): 572-7, 2003 Aug 15.
Article in English | MEDLINE | ID: mdl-12923446

ABSTRACT

BACKGROUND: Eosinophils participate in allograft rejection when donor-reactive helper T lymphocytes are T-helper type 2 (Th2)-biased. Whereas the involvement of interleukin (IL)-4 and IL-5 in these forms of rejection is well established, the role of IL-9, another Th2-type cytokine promoting eosinophilia, has not been determined. METHODS: We first used real-time polymerase chain reaction to quantify IL-9 mRNA in rejected allografts in a mouse model of fully mismatched heart transplantation in which recipients were devoid of CD8 T cells and developed a Th2 alloimmune response. We then compared allograft survival in wild-type versus IL-9-deficient mice depleted of CD8 T cells. Finally, we compared the fate of major histocompatibility complex class II-mismatched cardiac transplants from wild-type versus IL-9 transgenic donors to determine the influence of IL-9 overexpression within the graft. RESULTS: The Th2 alloimmune response in CD8-deficient mice was associated with the accumulation of IL-9 mRNA in the rejected graft. In IL-9-deficient recipients depleted of CD8 T cells, eosinophil infiltration of heart allografts did not develop, but rejection still occurred. In the major histocompatibility complex class II disparate model, heart allografts from IL-9 transgenic donors were acutely rejected, whereas grafts from wild-type donors did not develop rejection. Acute rejection of IL-9 transgenic hearts was associated with massive eosinophil infiltration and prevented by neutralization of either IL-4 or IL-5. CONCLUSION: IL-9 is critically involved in heart transplant eosinophilia in conjunction with IL-4 and IL-5.


Subject(s)
Eosinophils/physiology , Graft Rejection/physiopathology , Heart Transplantation , Interleukin-9/physiology , Animals , Eosinophilia/immunology , Interleukin-4/physiology , Interleukin-5/physiology , Interleukin-9/analysis , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Polymerase Chain Reaction , RNA, Messenger/analysis , Th2 Cells/immunology , Transplantation, Homologous
SELECTION OF CITATIONS
SEARCH DETAIL
...