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1.
Clin Exp Immunol ; 188(1): 12-21, 2017 04.
Article in English | MEDLINE | ID: mdl-27880974

ABSTRACT

Maintenance of peripheral tolerance requires a balance between autoreactive conventional T cells (Tconv ) and thymically derived forkhead box protein 3 (FoxP3)+ regulatory T cells (tTregs ). Considerable controversy exists regarding the similarities/differences in T cell receptor (TCR) repertoires expressed by Tconv and tTregs . We generated highly purified populations of human adult and cord blood Tconv and tTregs based on the differential expression of CD25 and CD127. The purity of the sorted populations was validated by intracellular staining for FoxP3 and Helios. We also purified an overlap group of CD4 T cells from adult donors to ensure that considerable numbers of shared clonotypes could be detected when present. We used deep sequencing of entire TCR-ß CDR3 sequences to analyse the TCR repertoire of Tconv and tTregs . Our studies suggest that both neonatal and adult human Tconv and tTreg cells are, in fact, entirely distinct CD4 T cell lineages.


Subject(s)
Forkhead Transcription Factors/metabolism , High-Throughput Nucleotide Sequencing , Phenotype , Receptors, Antigen, T-Cell, alpha-beta/genetics , T-Lymphocyte Subsets/metabolism , Biomarkers , Clonal Evolution , Complementarity Determining Regions/genetics , Humans , Immunophenotyping , Receptors, Antigen, T-Cell, alpha-beta/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , VDJ Exons/genetics
2.
Cytogenet Genome Res ; 105(2-4): 292-301, 2004.
Article in English | MEDLINE | ID: mdl-15237218

ABSTRACT

The spatial organization of genomes within the mammalian cell nucleus is non-random. The functional relevance of spatial genome organization might be in influencing gene expression programs as cells undergo changes during development and differentiation. To gain insight into the plasticity of genomes in space and time and to correlate the activity of specific genes with their nuclear position, we systematically analyzed the spatial genome organization in differentiating mouse T-cells. We find significant global reorganization of centromeres, chromosomes and gene loci during the differentiation process. Centromeres were repositioned from a preferentially internal distribution in undifferentiated cells to a preferentially peripheral position in differentiated CD4+ and CD8+ cells. Chromosome 6, containing the differentially expressed T-cell markers CD4 and CD8, underwent differential changes in position depending on whether cells differentiated into CD4+ or CD8+ thymocytes. Similarly, the two marker loci CD4 and CD8 showed distinct behavior in their position relative to the chromosome 6 centromere at various stages of differentiation. Our results demonstrate that significant spatial genome reorganization occurs during differentiation and indicate that the relationship between dynamic genome topology and single gene regulation is highly complex.


Subject(s)
Genome , Lymphopoiesis/genetics , T-Lymphocytes/cytology , Animals , CD4 Antigens/genetics , CD8 Antigens/genetics , Centromere , Chromosome Mapping , Mice , Mice, Inbred C57BL
4.
Immunol Rev ; 182: 58-67, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11722623

ABSTRACT

Depletion of the minor ( approximately 10%) subpopulation of CD4+ T cells that co-expresses CD25 (interleukin (IL)-2 receptor alpha-chain) by thymectomy of neonates on the third day of life or by treatment of adult CD4+ T cells with anti-CD25 and complement results in the development of organ-specific autoimmunity. Autoimmune disease can be prevented by reconstitution of the animals with CD4+ CD25+ cells. CD4+ CD25+-mediated protection of autoimmune gastritis does not require the suppressor cytokines IL-4, IL-10, or transforming growth factor (TGF)-beta. Mice that express a transgenic T-cell receptor (TCR) derived from a thymectomized newborn that recognizes the gastric parietal cell antigen H/K ATPase all develop severe autoimmune gastritis very early in life. CD4+ CD25+ T cells are also powerful suppressors of the activation of both CD4+ and CD8+ T cells in vitro. Suppression is mediated by a cell contact-dependent, cytokine-independent T-T interaction. Activation of CD4+ CD25+ via their TCR generates suppressor effector cells that are capable of non-specifically suppressing the activation of any CD4+ or CD8+ T cell. Activation of suppressor effector function is independent of co-stimulation mediated by CD28/CTLA-4 interactions with CD80/CD86. We propose that CD4+ CD25+ T cells recognize organ-specific antigens, are recruited to sites of autoimmune damage where they are activated by their target antigen, and then physically interact with autoreactive CD4+ or CD8+ effector cells to suppress the development of autoimmune disease.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Lymphocyte Activation , Receptors, Interleukin-2/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Autoimmune Diseases/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cell Division , Humans , Organ Specificity , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Thymus Gland/cytology , Thymus Gland/immunology , Transgenes
5.
Immunology ; 104(1): 28-36, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11576217

ABSTRACT

Thymic shared antigen-1 (TSA-1) is a member of the Ly-6 family of glycosyl-phosphatidylinositol (GPI)-linked proteins. While it has been proposed that TSA-1 may play a role in thymic development, a physiological ligand for this antigen has not been identified. Here we report that a monoclonal antibody (mAb) to TSA-1, generated by immunizing a hamster with CD40 ligand (CD40L)-activated B cells, interferes with the function of FcgammaRIIB on splenic B cells and the B-cell lymphoma cell line, M12, by binding to TSA on the same cells. The interaction of anti-TSA with FcgammaRIIB resulted in an inhibition of the ability of the FcgammaRIIB to cross-link and/or aggregate soluble anti-CD3 or soluble anti-Cbeta T-cell receptor (TCR), leading to an inhibition of induction of expression of CD25 and CD69, interleukin (IL)-2 production and proliferation of naive T cells. Cross-blocking studies with mAbs strongly suggested that a physical association exists between TSA-1 and the FcgammaRIIB on the surface of activated B cells and favour the view that a functional intermolecular association exists between these two distinct membrane antigens.


Subject(s)
Membrane Proteins/immunology , Receptors, IgG/antagonists & inhibitors , Animals , Antibodies, Monoclonal/immunology , Antigen-Presenting Cells/immunology , Antigens, CD/immunology , B-Lymphocytes/immunology , Binding, Competitive/immunology , CD4-Positive T-Lymphocytes/immunology , CD40 Ligand/immunology , Cell Culture Techniques , Cricetinae , Female , Lymphocyte Activation/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Receptors, IgG/immunology , Tissue Distribution
6.
Microbes Infect ; 3(11): 919-27, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11564440

ABSTRACT

CD4(+)CD25(+) T cells regulate the activity of autoreactive T cells. Depletion of these cells results in the development of a wide-spectrum of organ-specific autoimmune diseases. In vitro model systems have been developed to study the function of these potent suppressor cells. Following their activation via their T-cell receptor, they downregulate the responses of CD25(-) effectors by a T-T interaction.


Subject(s)
Autoimmune Diseases/immunology , CD4-Positive T-Lymphocytes/immunology , Gastritis/immunology , Organ Specificity/immunology , Receptors, Interleukin-2/metabolism , Animals , Autoimmune Diseases/prevention & control , Disease Models, Animal , Down-Regulation/immunology , Gastritis/prevention & control , Humans , Mice , T-Lymphocyte Subsets/immunology
8.
J Exp Med ; 194(2): 143-53, 2001 Jul 16.
Article in English | MEDLINE | ID: mdl-11457889

ABSTRACT

Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12-mediated interferon (IFN)-gamma production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor alpha chain (IL-18Ralpha) expression. The majority of peripheral CD4(+) T cells constitutively expressed the IL-18Ralpha. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18Ralpha expression was observed. IL-12-mediated upregulation of IL-18Ralpha required IFN-gamma. Activated CD4(+) T cells that expressed low levels of IL-18Ralpha could produce IFN-gamma when stimulated with the combination of IL-12 and IL-18, while CD4(+) cells which expressed high levels of IL-18Ralpha could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Ralpha expression. Both IL-4(-/)- and signal transducer and activator of transcription (Stat)6(-/)- T cells expressed higher levels of IL-18Ralpha after TCR stimulation. Furthermore, activated T cells from Stat6(-/)- mice produced more IFN-gamma in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18Ralpha by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Interleukin-4/metabolism , Receptors, Interleukin/metabolism , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation , Female , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Interleukin-12/pharmacology , Interleukin-18/pharmacology , Interleukin-18 Receptor alpha Subunit , Interleukin-4/genetics , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, Antigen, T-Cell/metabolism , Receptors, Interleukin/chemistry , Receptors, Interleukin-18 , STAT6 Transcription Factor , Th1 Cells/cytology , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/cytology , Th2 Cells/immunology , Th2 Cells/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism
9.
J Immunol ; 167(3): 1137-40, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11466326

ABSTRACT

CD4(+)CD25(+) regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4(+)CD25(-) T cells and are potent suppressors of CD4(+)CD25(-) T cell activation in vitro. We demonstrate that CD4(+)CD25(+) T cells also suppress both proliferation and IFN-gamma production by CD8(+) T cells induced either by polyclonal or Ag-specific stimuli. CD4(+)CD25(+) T cells inhibit the activation of CD8(+) responders by inhibiting both IL-2 production and up-regulation of IL-2Ralpha-chain (CD25) expression. Suppression is mediated via a T-T interaction as activated CD4(+)CD25(+) T cells suppress the responses of TCR-transgenic CD8(+) T cells stimulated with soluble peptide-MHC class I tetramers in the complete absence of APC. These results broaden the immunoregulatory role played by CD4(+)CD25(+) T cells in the prevention of autoimmune diseases, but also raise the possibility that they may hinder the induction of effector CD8(+) T cells to tumor or foreign Ags.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Lymphocyte Activation/immunology , Receptors, Interleukin-2/biosynthesis , T-Lymphocyte Subsets/immunology , Animals , Cells, Cultured , Coculture Techniques , Dose-Response Relationship, Immunologic , Female , Lymphocyte Activation/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes, Regulatory/immunology
10.
Eur J Immunol ; 31(7): 2094-103, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11449363

ABSTRACT

The development of mouse models of human organ-specific autoimmune diseases has been hampered by the need to immunize mice with autoantigens in potent adjuvants. Even autoantigen-specific T cell receptor transgenic models of autoimmunity have proven to be complex as the transgenic mice frequently fail to develop disease spontaneously. We have isolated a CD4(+) T cell clone (TxA23)that recognizes the gastric parietal cell antigen, H/K ATPase alpha-chain(630-641), from a mouse with autoimmune gastritis that developed after thymectomy on day 3 of life. The T cell receptor alpha and beta genes from this clone were used to generate A23 transgenic mice. All A23 transgenic animals spontaneously developed severe autoimmune gastritis, and evidence of disease was detected as early as day 10 of life. Gastritis could be transferred to immunocompromised mice with a limited number of transgenic thymocytes (10(3)), but as many as 10(7) induced only mild disease in wild-type animals. Due to the complete penetrance of spontaneous disease, identity of the auto-antigen, susceptibility to immunoregulation, and close relation to autoimmune gastritis in man, A23 transgenic mice represent a unique CD4(+) T cell-mediated disease model for understanding the multiple factors regulating organ-specific autoimmunity.


Subject(s)
Autoimmune Diseases/immunology , Autoimmunity , Disease Models, Animal , Gastritis/immunology , Genes, T-Cell Receptor , Amino Acid Sequence , Animals , Autoantigens/immunology , Autoimmune Diseases/pathology , Base Sequence , CD4-Positive T-Lymphocytes/immunology , Gastritis/pathology , Gene Rearrangement, T-Lymphocyte , H(+)-K(+)-Exchanging ATPase/immunology , Lymph Nodes/immunology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Molecular Sequence Data , Receptors, Interleukin-2/immunology , T-Lymphocytes, Regulatory/immunology , Thymus Gland/immunology , Thymus Gland/transplantation
12.
J Immunol ; 166(9): 5712-9, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11313413

ABSTRACT

B10.Q mice are normally susceptible to the induction of collagen-induced arthritis. We noted that one subline of B10.Q mice, B10.Q/J, was completely resistant to disease induction when immunized with collagen in CFA. B10.Q/J mice have a global defect in the generation of Th1 responses, and Ag-specific T cells derived from this strain failed to produce IFN-gamma. Because T cells from these mice could produce normal amounts of IFN-gamma when activated by IL-12/IL-18-independent stimuli, the defect appeared to be a failure to respond to IL-12. This defect extended to NK cells, which also failed to produce IFN-gamma when stimulated by IL-12. The capacity of NK cells, but not activated T cells, to produce IFN-gamma in response to IL-12 could be partially restored by IL-18. The expression of the IL-12R beta1- and beta2-chains on T cells and NK cells from B10.Q/J mice was normal. However, activated T cells from B10.Q/J mice did not signal normally through the IL-12R and manifested a defect in their capacity to phosphorylate Stat4. This defect was partial in that it could be overcome by increasing both the concentration of IL-12 and the incubation times in the Stat4 phosphorylation assays. Because Stat4 function is apparently intact in B10.Q/J mice, the defect in IL-12 signaling can be localized between the IL-12R complex and Stat4. This subtle abnormality in IL-12 responsiveness results in a profound defect in the generation of Th1 cells and the development of autoimmune disease.


Subject(s)
Genetic Predisposition to Disease , Interleukin-12/deficiency , Interleukin-12/genetics , Mice, Inbred C57BL/genetics , Signal Transduction/genetics , Signal Transduction/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , DNA-Binding Proteins/metabolism , Drug Synergism , H-2 Antigens/genetics , Interferon-gamma/biosynthesis , Interferon-gamma/deficiency , Interferon-gamma/genetics , Interleukin-12/metabolism , Interleukin-12/physiology , Interleukin-18/pharmacology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocyte Activation/genetics , Male , Mice , Phosphorylation , Receptors, Interleukin/biosynthesis , Receptors, Interleukin/physiology , Receptors, Interleukin-12 , STAT4 Transcription Factor , Spleen/cytology , Spleen/immunology , Th1 Cells/immunology , Th1 Cells/metabolism , Trans-Activators/metabolism
13.
Clin Immunol ; 98(1): 109-18, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11141333

ABSTRACT

Collagen-induced arthritis is an animal model of inflammatory polyarthritis that is induced in susceptible strains of rats and mice by intradermal immunization with heterologous type II collagen emulsified in complete Freund's adjuvant. Previous studies have demonstrated that disease induction is highly MHC-restricted, with only mice of H-2(q) or H-2(r) haplotypes being susceptible. We have used a panel of both susceptible and resistant strains of mice in which either IFN-gamma or IL-10 signaling has been abolished by gene deletion and show that disease can be readily induced in several resistant strains of the H-2(b) and H-2(d) haplotype; susceptibility was highly dependent on IL-12. IL-4 was also shown to be crucial for disease induction in this model. These results suggest that both Th1 and Th2 cytokines may be important in the etiopathogenesis of disease and that disease susceptibility may be a function of a dysregulated cytokine environment.


Subject(s)
Arthritis, Experimental/immunology , Animals , Antibodies/therapeutic use , Antibody Formation , Collagen/immunology , Cytokines/biosynthesis , Cytokines/pharmacology , Disease Susceptibility/immunology , Haplotypes , Interferon-gamma/deficiency , Interleukin-10/deficiency , Interleukin-12/immunology , Interleukin-12/pharmacology , Major Histocompatibility Complex/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
14.
Curr Protoc Immunol ; Appendix 3: Appendix 3D, 2001 May.
Article in English | MEDLINE | ID: mdl-18432656

ABSTRACT

A number of protocols in Current Protocols in Immunology use as their end-point the determination of cell proliferation by determining the incorporation of [(3)H]thymidine into cellular DNA. This appendix presents a protocol in which the radioactive label is added during the last 4 to 24 hr of the culture. A semiautomated cell harvesting apparatus is then used to lyse the cells with water and precipitate the labeled DNA on glass fiber filters. The filter pads are then dried and counted by standard liquid scintillation counting techniques in a scintillation counter.


Subject(s)
Cell Growth Processes/physiology , DNA/biosynthesis , Thymidine/pharmacokinetics , Tritium/analysis , Cells, Cultured , DNA/genetics , Scintillation Counting/methods , Thymidine/metabolism
16.
Annu Rev Immunol ; 18: 423-49, 2000.
Article in English | MEDLINE | ID: mdl-10837065

ABSTRACT

Clonal deletion of autoreactive T cells in the thymus is not the sole mechanism for the induction of tolerance to self-antigens since partial depletion of peripheral CD4(+) T cells from neonatal and adult animals results in the development of organ-specific autoimmunity. Reconstitution of these immunodeficient animals with populations of regulatory CD4(+)T cells prevents the development of autoimmunity. The lineage of regulatory CD4(+) T cells is generated in the thymus and can be distinguished from effector cells by the expression of unique membrane antigens. The target antigens for these suppressor populations and their mechanisms of action remain poorly defined. Depletion of regulatory T cells may be useful in the induction of immunity to weak antigens, such as tumor-specific antigens. Conversely, enhancement of regulatory T cell function may be a useful adjunct to the therapy of autoimmune diseases and for prevention of allograft rejection.


Subject(s)
Autoimmunity/immunology , T-Lymphocytes/immunology , Animals , Autoimmune Diseases/immunology , Humans , Lymphocyte Depletion , Thymus Gland/cytology
17.
J Immunol ; 164(11): 5683-8, 2000 Jun 01.
Article in English | MEDLINE | ID: mdl-10820244

ABSTRACT

The mechanism of action of microbial adjuvants in promoting the differentiation of autoimmune effector cells remains to be elucidated. We demonstrate that CpG-containing oligodeoxynucleotides (ODN) can completely substitute for heat-killed mycobacteria in the priming of encephalitogenic myelin-reactive T cells in vivo. The adjuvanticity of the CpG ODN was secondary to their direct ability to induce IL-12 or to act synergistically with endogenous IL-12 to promote Th1 differentiation and encephalitogenicity. T cells primed in the absence of CpG with Ag and IFA alone appeared to be in a transitional state and had not undergone differentiation along a conventional Th pathway. Unlike Th2 cells, they expressed low levels of the IL-12R beta 2 subunit and retained the ability to differentiate into encephalitogenic effectors when reactivated in vitro under Th1-polarizing conditions. These results support the use of CpG ODN as adjuvants but also suggest that they could potentially trigger autoimmune disease in a susceptible individual.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Autoantigens/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Lipids , Lymphocyte Activation/immunology , Oligodeoxyribonucleotides , Oligonucleotides/immunology , T-Lymphocyte Subsets/immunology , Amino Acid Sequence , Animals , Cells, Cultured , Female , Freund's Adjuvant/administration & dosage , Injections, Subcutaneous , Interleukin-12/physiology , Mice , Mice, Inbred Strains , Molecular Sequence Data , Myelin Basic Protein/immunology , Oligonucleotides/administration & dosage , Th1 Cells/immunology
18.
Eur J Immunol ; 30(4): 1113-9, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10760800

ABSTRACT

IL-18 was originally described as a cytokine which induced IFN-gamma production by established Th1 cells in an IL-12-independent manner. However, subsequent studies demonstrated that exogenous IL-18 in the absence of IL-12 failed to drive Th1 differentiation of naive cells and induced IFN-gamma from established Th1 cells only in combination with IL-12. We have examined the role of endogenous IL-18 in controlling Th1 lineage commitment. When naive TCR-transgenic T cells were stimulated with antigen, anti-IL-18 antibodies resulted in partial inhibition of IFN-gamma production, but did not inhibit Th1 differentiation. To distinguish whether the inhibitory effect of anti-IL-18 antibodies was mediated directly by blocking IFN-gamma production or indirectly by blocking IL-12Rbeta2 up-regulation, naive T cells from IL-12 - / - mice were stimulated with anti-CD3 and IL-18. These cells failed to produce IFN-gamma, but markedly up-regulated IL-12Rbeta2 expression. We propose that the major effect of IL-18 on Th1 development is mediated by up-regulation of IL-12Rbeta2 expression, thereby enhancing IL-12-mediated signaling. The enhancement of IL-12Rbeta2 expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development.


Subject(s)
Interferon-gamma/biosynthesis , Interleukin-12/pharmacology , Interleukin-18/pharmacology , Receptors, Interleukin/metabolism , Th1 Cells/metabolism , Amino Acid Sequence , Animals , Antibodies/immunology , Antibodies/pharmacology , Autoimmunity/drug effects , Autoimmunity/immunology , CD3 Complex/immunology , Cell Differentiation/drug effects , Cells, Cultured , Encephalomyelitis, Autoimmune, Experimental/immunology , Gene Deletion , Interferon-gamma/antagonists & inhibitors , Interleukin-12/antagonists & inhibitors , Interleukin-12/genetics , Interleukin-12/immunology , Interleukin-18/antagonists & inhibitors , Interleukin-18/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Molecular Sequence Data , Myelin Basic Protein/immunology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Interleukin/chemistry , Receptors, Interleukin/genetics , Receptors, Interleukin-12 , Signal Transduction/drug effects , Th1 Cells/cytology , Th1 Cells/drug effects , Th1 Cells/immunology , Up-Regulation/drug effects
19.
J Immunol ; 164(1): 100-6, 2000 Jan 01.
Article in English | MEDLINE | ID: mdl-10604999

ABSTRACT

Costimulation mediated by the interactions of the B7 Ags (CD80/CD86) on APC with CD28 on the responding T cell regulates the magnitude of the immune response and may influence Th1/Th2 development. The IL-12Rbeta2 subunit plays a critical role in maintaining IL-12 responsiveness and controlling Th1 lineage commitment. We demonstrate that IL-2 and IL-12 resulting from CD28/B7 interactions both play a critical role in the induction of expression of the IL-12Rbeta2 subunit and as a result the differentiation of pathogenic autoreactive effector cells. These findings suggest that targeting IL-2 and IL-12 simultaneously may be effective in the treatment of Th1-mediated autoimmunity.


Subject(s)
B7-1 Antigen/physiology , CD28 Antigens/physiology , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunoconjugates , Interleukin-12/biosynthesis , Receptors, Interleukin/biosynthesis , Signal Transduction/immunology , Abatacept , Adjuvants, Immunologic/physiology , Animals , Antigens, CD , Antigens, Differentiation/pharmacology , CD28 Antigens/genetics , CD40 Antigens/metabolism , CD40 Ligand , CTLA-4 Antigen , Cell Differentiation/immunology , Encephalomyelitis, Autoimmune, Experimental/etiology , Interferon-gamma/biosynthesis , Interleukin-12/pharmacology , Interleukin-12/physiology , Interleukin-2/physiology , Ligands , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mice, Transgenic , Receptors, Interleukin/physiology , Receptors, Interleukin-12 , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
20.
J Immunol ; 164(1): 183-90, 2000 Jan 01.
Article in English | MEDLINE | ID: mdl-10605010

ABSTRACT

CD4+CD25+ T cells represent a unique population of "professional" suppressor T cells that prevent induction of organ-specific autoimmune disease. In vitro, CD4+CD25+ cells were anergic to simulation via the TCR and when cultured with CD4+CD25- cells, markedly suppressed polyclonal T cell proliferation by specifically inhibiting the production of IL-2. Suppression was cytokine independent, cell contact dependent, and required activation of the suppressors via their TCR. Further characterization of the CD4+CD25+ population demonstrated that they do not contain memory or activated T cells and that they act through an APC-independent mechanism. CD4+CD25+ T cells isolated from TCR transgenic (Tg) mice inhibited responses of CD4+CD25- Tg T cells to the same Ag, but also inhibited the Ag-specific responses of Tg cells specific for a distinct Ag. Suppression required that both peptide/MHC complexes be present in the same culture, but the Ags could be presented by two distinct populations of APC. When CD4+CD25+ T cells were cultured with anti-CD3 and IL-2, they expanded, remained anergic, and in the absence of restimulation via their TCR, suppressed Ag-specific responses of CD4+CD25- T cells from multiple TCR transgenics. Collectively, these data demonstrate that CD4+CD25+ T cells require activation via their TCR to become suppressive, but once activated, their suppressor effector function is completely nonspecific. The cell surface molecules involved in this T-T interaction remain to be characterized.


Subject(s)
CD4 Antigens/immunology , Epitopes, T-Lymphocyte/immunology , Receptors, Interleukin-2/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Animals , CD4 Antigens/biosynthesis , CD4 Antigens/genetics , Cell Cycle/immunology , Cell Line , Cell Separation , Epitopes, T-Lymphocyte/genetics , Female , Immunologic Memory , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Interleukin-2/biosynthesis , Receptors, Interleukin-2/genetics , Signal Transduction/immunology
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