ABSTRACT
CD69 is highly expressed by lymphocytes at mucosal surfaces. We aimed to investigate the role of CD69 in mucosal immune responses. The expression of CD69 by CD4 T cells isolated from the spleen, mesenteric lymph nodes, small intestinal lamina propria, and colonic lamina propria was determined in specific pathogen-free B6 and TCR transgenic animals, as well as in germ-free B6 mice. Transfer colitis was induced by transplanting RAG(-/-) mice with B6 or CD69(-/-)CD45RB(high) CD4 T cells. CD69 expression by CD4 T cells is induced by the intestinal microflora, oral delivery of specific Ag, and type I IFN (IFN-I) signals. CD4 T cells from CD69(-/-) animals produce higher amounts of the proinflammatory cytokines IFN-γ, TNF-α, and IL-21, whereas the production of TGF-ß1 is decreased. CD69-deficient CD4 T cells showed reduced potential to differentiate into Foxp3(+) regulatory T cells in vivo and in vitro. The transfer of CD69(-/-)CD45RB(high) CD4 T cells into RAG(-/-) hosts induced an accelerated colitis. Oral tolerance was impaired in CD69(-/-) and IFN-I receptor 1-deficient mice when compared with B6 and OT-II × RAG(-/-) animals. Polyinosinic-polycytidylic acid treatment of RAG(-/-) mice transplanted with B6 but not CD69(-/-) or IFN-I receptor 1-deficient CD45RB(high) CD4 T cells attenuated transfer colitis. CD69 deficiency led to the increased production of proinflammatory cytokines, reduced Foxp3(+) regulatory T cell induction, impaired oral tolerance, and more severe colitis. Hence, the activation Ag CD69 plays an important role in regulating mucosal immune responses.
Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , CD4-Positive T-Lymphocytes/immunology , Colitis/immunology , Interferon Type I/metabolism , Lectins, C-Type/metabolism , Adoptive Transfer , Animals , Antigens, CD/genetics , Antigens, Differentiation, T-Lymphocyte/genetics , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/transplantation , Forkhead Transcription Factors/biosynthesis , Immunity, Mucosal , Interferon-gamma/biosynthesis , Interleukins/biosynthesis , Intestines/immunology , Intestines/microbiology , Lectins, C-Type/deficiency , Lectins, C-Type/genetics , Leukocyte Common Antigens/genetics , Leukocyte Common Antigens/immunology , Lymph Nodes/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mucous Membrane/immunology , Poly I-C/administration & dosage , Poly I-C/pharmacology , Spleen/immunology , T-Lymphocytes, Regulatory/immunology , Transforming Growth Factor beta1/biosynthesis , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
IL-20 was discovered 10 years ago as a new member of the IL-10 family of cytokines. IL-20 shares the highest amino-acid sequence identity with IL-10, IL-24 and IL-19. IL-20 is secreted by immune cells and activated epithelial cells like keratinocytes. A high expression of the corresponding IL-20 receptor chains is detected on epithelial cells. In terms of function, IL-20 might therefore mediate a crosstalk between epithelial cells and tissue-infiltrating immune cells under inflammatory conditions. Transgenic and knockout mouse models for some cytokines and receptors of the IL-10-type cytokines have provided new insights into the biology of this family. This review will focus on the biological functions of IL-20 and its receptors within the IL-10 cytokine network.
Subject(s)
Interleukins/physiology , Receptors, Interleukin/physiology , Animals , HumansABSTRACT
Coinhibitors and costimulators control intrahepatic T cell responses that trigger acute hepatitis. We used the ConA-induced hepatitis model in the mouse to test if the coinhibitor herpes virus entry mediator (HVEM) modulates hepatitis-inducing T cell responses. Compared with ConA-injected, wild-type (wt) C57BL/6 (B6) mice, HVEM-deficient (HVEM(-/-)) B6 mice showed lower serum transaminase levels and lower proinflammatory IFN-gamma, but higher protective IL-22 serum levels and an attenuated liver histopathology. The liver type I invariant NKT cell population that initiates acute hepatitis in this model was reduced in HVEM(-/-) mice but their surface phenotype was similar to that of untreated or ConA-treated wt controls. In response to mitogen injection, liver invariant NKT cells from HVEM(-/-) B6 mice produced in vivo more IL-22 but lower amounts of IFN-gamma and IL-4 than wt controls. Bone marrow chimeras showed that HVEM deficiency of the liver nonparenchymal cell population, but not of the parenchymal cell population, mediated the attenuated course of the dendritic cell- and T cell-dependent ConA hepatitis. IL-22 is produced more efficiently by liver NKT cells from HVEM(-/-) than from wt mice, and its Ab-mediated neutralization of IL-22 aggravated the course of hepatitis in wt and HVEM(-/-) mice. Hence, HVEM expression promotes pathogenic, proinflammatory Th1 responses but down-modulates protective IL-22 responses of T cells in this model of acute hepatitis.
Subject(s)
Concanavalin A/pharmacology , Hepatitis/immunology , Interleukins/immunology , Receptors, Tumor Necrosis Factor, Member 14/deficiency , Receptors, Tumor Necrosis Factor, Member 14/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Animals , Hepatitis/genetics , Hepatitis/metabolism , Interleukins/blood , Mice , Mice, Knockout , Receptors, Tumor Necrosis Factor, Member 14/genetics , Receptors, Tumor Necrosis Factor, Member 14/metabolism , Interleukin-22ABSTRACT
The recently described cytokines IL-19, IL-20, and IL-24 share structural homology with IL-10 and are therefore classified as members of the IL-10 family of cytokines. Although it has long been speculated that signaling by their heterodimeric receptor complexes (IL-20R1/IL-20R2 and IL-22R/IL-20R2) influences immunological processes, the target cells for this group of cytokines are still unclear. By generating a knockout mouse strain deficient for the common IL-20R beta-chain (IL-20R2), we show that IFN-gamma and IL-2 secretion is significantly elevated after stimulation of IL-20R2-/--deficient CD8 and CD4 T cells with Con A or anti-CD3/CD28 in vitro. IL-10 secretion by activated IL-20R2-/- CD4 cells was diminished. Consistent with our in vitro results, significantly more Ag-specific CD8 IFN-gamma+ and CD4 IFN-gamma+ T cells developed to locally applied DNA vaccines in IL-20R2-deficient mice. In a T cell-dependent model of contact hypersensitivity, IL-20R2 knockout mice were more sensitive to the contact allergen trinitro-chloro-benzene. Thus, IL-20R2 signaling directly regulates CD8 and CD4 T cell answers in vitro and in vivo. For the first time, we provide evidence that IL-19, IL-20, and IL-24 are part of a signaling network that normally down-modulates T cell responses in mice.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Down-Regulation/immunology , Epitopes, T-Lymphocyte/immunology , Receptors, Interleukin/physiology , Signal Transduction/immunology , Allergens/administration & dosage , Allergens/immunology , Animals , Cells, Cultured , Coculture Techniques , Dermatitis, Contact/genetics , Dermatitis, Contact/immunology , Down-Regulation/genetics , Female , Lymphocyte Activation/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Picryl Chloride/administration & dosage , Picryl Chloride/immunology , Receptors, Interleukin/deficiency , Receptors, Interleukin/genetics , Signal Transduction/genetics , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunologyABSTRACT
BACKGROUND/AIMS: The biological functions of the recently discovered IL-10-related cytokines IL-19, IL-20, IL-22, IL-24 and their receptors IL-20R1, IL-20R2 and IL-22R are not clear. Therefore, the expression of these cytokines and their receptors in the hepatic acute phase response to LPS was analysed. Type I interferons have important immunomodulatory functions in bacterial infections. We investigated if they influence release and organ-specific expression of TNF, IL-6 and IL-10 and the responsiveness of liver to IL-10 related cytokines during the reaction to LPS in vivo. METHODS: B6 and congenic IFNAR-/- mice were intraperitoneally injected with 5mg/kg LPS. Systemic release of cytokines was quantified by ELISA. Organ-specific expression of cytokines and their receptors was evaluated by (semi quantitative or quantitative) RT-PCR. RESULTS: The cytokines IL-19, IL-22 and the IL-20R2 receptor subunit are up-regulated by LPS in the liver of normal mice. IFNalpha/beta enhance the secretion and expression of IL-6 and IL-10 during the response to LPS, but also the up-regulation of IL-20R2 expression. CONCLUSIONS: We show that the liver is a potential target for IL-19, IL-20 and IL-24. During an LPS response, IFNalpha/beta influence cytokine secretion and expression and possibly the response to IL-19 and IL-24.
