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1.
Eur J Immunol ; 46(1): 114-21, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26449668

ABSTRACT

The genus leishmania comprises different protozoan parasites which are causative agents of muco-cutaneous and systemic, potentially lethal diseases. After infection with the species Leishmania major, resistant mice expand Th1 cells which stimulate macrophages for Leishmania destruction. In contrast, susceptible mice generate Th2 cells which deactivate macrophages, leading to systemic spread of the pathogens. Th-cell differentiation is determined within the first days, and Th2 cell differentiation requires IL-4, whereby the initial IL-4 source is often unknown. Mast cells are potential sources of IL-4, and hence their role in murine leishmaniasis has previously been studied in mast cell-deficient Kit mutant mice, although these mice display immunological phenotypes beyond mast cell deficiency. We therefore readdressed this question by infecting Kit-independent mast cell-deficient mice that are Th1 (C57BL/6 Cpa(Cre) ) or Th2 (BALB/c Cpa(Cre) ) prone with L. major. Using different parasite doses and intra- or subcutaneous infection routes, the results demonstrate no role of mast cells on lesion size development, parasite load, immune cell phenotypes expanding in draining lymph nodes, and cytokine production during murine cutaneous leishmaniasis. Thus, other cell types such as ILCs or T cells have to be considered as primary source of Th2-driving IL-4.


Subject(s)
Leishmaniasis, Cutaneous/immunology , Mast Cells/immunology , Th2 Cells/immunology , Animals , Cell Differentiation/immunology , Disease Models, Animal , Disease Susceptibility , Leishmania major , Leishmaniasis, Cutaneous/parasitology , Lymphocyte Activation/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Mutant Strains , Parasite Load
2.
Nat Commun ; 6: 8576, 2015 Oct 13.
Article in English | MEDLINE | ID: mdl-26815406

ABSTRACT

Regulatory T-cells induced via IL-2 and TGFß in vitro (iTreg) suppress immune cells and are potential therapeutics during autoimmunity. However, several reports described their re-differentiation into pathogenic cells in vivo and loss of their key functional transcription factor (TF) FOXP3 after T-cell antigen receptor (TCR)-signalling in vitro. Here, we show that TCR-activation antagonizes two necessary TFs for foxp3 gene transcription, which are themselves regulated by phosphorylation. Although the tyrosine phosphatase PTPN2 is induced to restrain IL-2-mediated phosphorylation of the TF STAT5, expression of the TF FOXO1 is downregulated and miR-182, a suppressor of FOXO1 expression, is upregulated. TGFß counteracts the FOXP3-depleting TCR-signal by reassuring FOXO1 expression and by re-licensing STAT5 phosphorylation. Overexpressed phosphorylation-independent active versions of FOXO1 and STAT5 or knockdown of PTPN2 restores FOXP3 expression despite TCR-signal and absence of TGFß. This study suggests novel targets for stabilisation and less dangerous application of iTreg during devastating inflammation.


Subject(s)
Forkhead Transcription Factors/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes, Regulatory/metabolism , Animals , Blotting, Western , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Female , Flow Cytometry , Forkhead Box Protein O1 , Forkhead Transcription Factors/genetics , Male , Mice , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , Receptors, Antigen, T-Cell/genetics
3.
PLoS Negl Trop Dis ; 7(7): e2322, 2013.
Article in English | MEDLINE | ID: mdl-23875052

ABSTRACT

BACKGROUND: For effective control of visceral leishmaniasis (VL) in East Africa, new rapid diagnostic tests are required to replace current tests with low sensitivity. The aim of this study is to improve diagnosis of VL in East Africa by testing a new antigen from an autochthonous L. donovani strain in Sudan. METHODOLOGY AND PRINCIPLE FINDINGS: We cloned, expressed and purified a novel recombinant protein antigen of L. donovani from Sudan, designated rKLO8, that contains putative conserved domains with significant similarity to the immunodominant kinesin proteins of Leishmania. rKLO8 exhibited 93% and 88% amino acid identity with cloned kinesin proteins of L. infantum (synonymous L. chagasi) (K39) and L. donovani (KE16), respectively. We evaluated the diagnostic efficiency of the recombinant protein in ELISA for specific detection of VL patients from Sudan. Data were compared with a rK39 ELISA and two commercial kits, the rK39 strip test and the direct agglutination test (DAT). Of 106 parasitologically confirmed VL sera, 104 (98.1%) were tested positive by rKLO8 as compared to 102 (96.2%) by rK39. Importantly, the patients' sera showed increased reactivity with rKLO8 than rK39. Specificity was 96.1% and 94.8% for rKLO8- and rK39 ELISAs, respectively. DAT showed 100% specificity and 94.3% sensitivity while rK39 strip test performed with 81.1% sensitivity and 98.7% specificity. CONCLUSION: The increased reactivity of Sudanese VL sera with the rKLO8 makes this antigen a potential candidate for diagnosis of visceral leishmaniasis in Sudan. However, the suitability at the field level will depend on its performance in a rapid test format.


Subject(s)
Antibodies, Protozoan/blood , Antigens, Protozoan , Diagnostic Tests, Routine/methods , Leishmania donovani/immunology , Leishmaniasis, Visceral/diagnosis , Protozoan Proteins , Agglutination Tests/methods , Antigens, Protozoan/genetics , DNA, Protozoan/chemistry , DNA, Protozoan/genetics , Enzyme-Linked Immunosorbent Assay/methods , Humans , Leishmania donovani/genetics , Molecular Sequence Data , Protozoan Proteins/genetics , Recombinant Proteins/genetics , Sensitivity and Specificity , Sequence Analysis, DNA , Sudan
4.
J Clin Invest ; 123(1): 247-60, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23221338

ABSTRACT

IL-17-producing CD8+ T (Tc17) cells are detectible in multiple sclerosis (MS) lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a murine model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tc17 and Th17 cells and were resistant to EAE. After adoptive transfer of WT CD8+ T cells and subsequent immunization for EAE induction in these mice, the CD8+ T cells developed a Tc17 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4+ T cells alone did not evoke EAE, but when transferred together with CD8+ T cells, IL-17-producing CD4+ (Th17) T cells accumulated in the CNS and mice developed severe disease. Th17 accumulation and development of EAE required IL-17A production by CD8+ T cells, suggesting that Tc17 cells are required to promote CD4+ T cell-mediated induction of EAE. Accordingly, patients with early-stage MS harbored a greater number of Tc17 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tc17 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Th17 cell pathogenicity.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Central Nervous System/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Interleukin-17/immunology , Th17 Cells/immunology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Central Nervous System/metabolism , Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Humans , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/immunology , Interferon Regulatory Factors/metabolism , Interleukin-17/genetics , Interleukin-17/metabolism , Mice , Mice, Knockout , Th17 Cells/metabolism , Th17 Cells/pathology , Th17 Cells/transplantation
5.
Eur J Immunol ; 42(12): 3189-201, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22961652

ABSTRACT

Apart from conventional CD4(+) Th17 cells, the cytokines IL-17A and IL-22 can also be produced by γδ T cells, NK cells and lymphoid tissue inducer (LTi) cells. Th17 cells develop from precursor cells after T-cell receptor stimulation in the presence of TGF-ß, IL-6 and IL-23. In contrast, a subset of γδ T cells ("γδT17") is committed for fast IL-17 production already in the thymus; however, γδ T cells can also produce IL-17 after prolonged in vitro stimulation via their γδ T-cell receptor plus IL-23. Here, we show that γδ T-, LTi- and NKT cells differ extensively from Th17 cells in their signalling requirements for the generation of IL-17A and IL-22. While production of these cytokines by Th17 cells totally depends on the transcription factor interferon regulatory factor 4 (IRF4), IRF4 is irrelevant in the other cell types. As for γδ T cells, this finding pertains to both thymic commitment and prolonged in vitro culture. Furthermore, IL-17A-producing γδ T cells accumulate in the central nervous system of IRF4 deficient (Irf4(-/-)) mice during experimental autoimmune encephalomyelitis. IL-17A-producing WT and Irf4(-/-) γδ T cells equally express CCR6 and lack CD27. The underlying IRF4-independent pathway partially involves STAT3 during in vitro stimulation.


Subject(s)
Gene Expression Regulation/immunology , Interferon Regulatory Factors/immunology , Interleukin-17/immunology , Interleukins/immunology , Natural Killer T-Cells/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Animals , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental , Gene Expression Regulation/genetics , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Interleukin-17/biosynthesis , Interleukin-17/genetics , Interleukins/biosynthesis , Interleukins/genetics , Mice , Mice, Inbred BALB C , Mice, Knockout , Natural Killer T-Cells/metabolism , Natural Killer T-Cells/pathology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/genetics , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, CCR6/biosynthesis , Receptors, CCR6/genetics , Receptors, CCR6/immunology , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/immunology , STAT3 Transcription Factor/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Th17 Cells/pathology , Tumor Necrosis Factor Receptor Superfamily, Member 7/biosynthesis , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , Interleukin-22
6.
Proc Natl Acad Sci U S A ; 109(22): 8664-9, 2012 May 29.
Article in English | MEDLINE | ID: mdl-22552227

ABSTRACT

Follicular T-helper (T(FH)) cells cooperate with GL7(+)CD95(+) germinal center (GC) B cells to induce antibody maturation. Herein, we identify the transcription factor IRF4 as a T-cell intrinsic precondition for T(FH) cell differentiation and GC formation. After immunization with protein or infection with the protozoon Leishmania major, draining lymph nodes (LNs) of IFN-regulatory factor-4 (Irf4(-/-)) mice lacked GCs and GC B cells despite developing normal initial hyperplasia. GCs were also absent in Peyer's patches of naive Irf4(-/-) mice. Accordingly, CD4(+) T cells within the LNs and Peyer's patches failed to express the T(FH) key transcription factor B-cell lymphoma-6 and other T(FH)-related molecules. During chronic leishmaniasis, the draining Irf4(-/-) LNs disappeared because of massive cell death. Adoptive transfer of WT CD4(+) T cells or few L. major primed WT T(FH) cells reconstituted GC formation, GC B-cell differentiation, and LN cell survival. In support of a T-cell intrinsic IRF4 activity, Irf4(-/-) T(FH) cell differentiation was not rescued by close neighborhood to transferred WT T(FH) cells. Together with its known B lineage-specific roles during plasma cell maturation and class switch, our study places IRF4 in the center of antibody production toward T-cell-dependent antigens.


Subject(s)
Cell Differentiation/immunology , Germinal Center/immunology , Interferon Regulatory Factors/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adoptive Transfer , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/transplantation , Cell Survival/immunology , Female , Flow Cytometry , Gene Expression , Germinal Center/cytology , Germinal Center/metabolism , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Interleukins/genetics , Interleukins/immunology , Interleukins/metabolism , Leishmania major/immunology , Leishmaniasis, Cutaneous/genetics , Leishmaniasis, Cutaneous/immunology , Leishmaniasis, Cutaneous/parasitology , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Peyer's Patches/immunology , Peyer's Patches/metabolism , Plasma Cells/immunology , Plasma Cells/metabolism , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/transplantation
7.
Eur J Immunol ; 40(3): 671-6, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20049877

ABSTRACT

The NF-kappaB/Rel family member c-Rel was described to be required for the development of T(H)1 responses. However, the role of c-Rel in the differentiation of T(H)17 and regulatory CD4(+)Foxp3(+) T cells (Treg) remains obscure. Here, we show that in the absence of c-Rel, in vitro differentiation of pro-inflammatory T(H)17 cells is normal. In contrast, generation of inducible Treg (iTreg) within c-Rel-deficient CD4(+) T cells was severely hampered and correlated to reduced numbers of Foxp3(+) T cells in vivo. Mechanistically, in vitro conversion of naive CD4(+) T cells into iTreg was crucially dependent on c-Rel-mediated synthesis of endogenous IL-2. The addition of exogenous IL-2 was sufficient to rescue the development of c-Rel-deficient iTreg. Thus, c-Rel is essential for the development of Foxp3(+) Treg but not for T(H)17 cells via regulating the production of IL-2.


Subject(s)
Cell Differentiation/immunology , Forkhead Transcription Factors/immunology , Proto-Oncogene Proteins c-rel/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Regulatory/cytology , Animals , Blotting, Western , Cell Separation , Flow Cytometry , Interleukin-17/immunology , Interleukin-2/biosynthesis , Interleukin-2/immunology , Mice , Mice, Inbred C57BL , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology
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