477 research outputs found
A Role for Thymic Stromal Lymphopoietin in CD4+ T Cell Development
Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor α chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor γ chain, γc. We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, γc/TSLPR double KO mice had a greater lymphoid defect than γc KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in γc KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into γc KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti–IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4+ single positive thymocytes and peripheral T cells in vitro. Additionally, CD4+ T cells from TSLPR KO mice expanded less efficiently than WT CD4+ T cells in irradiated hosts, and TSLP preferentially expanded CD4+ T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4+ T cells
Stat5 Synergizes with T Cell Receptor/Antigen Stimulation in the Development of Lymphoblastic Lymphoma
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II–restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process
Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function
Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain (γc), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R−/− mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15
Regulatory B Cell (B10 Cell) Expansion during Listeria Infection Governs Innate and Cellular Immune Responses in Mice
Pathogens use numerous methods to subvert host immune responses, including the modulation of host IL-10 production by diverse cell types. However, the B cell sources of IL-10 and their overall influence on innate and cellular immune responses have not been well characterized during infections. Using Listeria as a model pathogen, infection drove the acute expansion of a small subset of regulatory B cells (B10 cells) that potently suppress inflammation and autoimmunity through the production of IL-10. Unexpectedly, spleen bacteria loads were 92–97% lower in B10 cell-deficient CD19−/− mice, in mice depleted of mature B cells, and in mice treated with CD22 mAb to preferentially deplete B10 cells before infection. By contrast, the adoptive transfer of wild type B10 cells reduced bacterial clearance by 38-fold in CD19−/− mice through IL-10-dependent pathways. B10 cell depletion using CD22 mAb significantly enhanced macrophage phagocytosis of Listeria and their production of IFN-γ, TNF-α, and nitric oxide ex vivo. Accelerated bacteria clearance following B10 cell depletion significantly reduced Ag-specific CD4+ T cell proliferation and cytokine production, but did not alter CD8+ T cell responses. B10 cell regulatory function during innate immune responses was nonetheless dependent on cognate interactions with CD4+ T cells since B10 cells deficient in IL-10, MHC-II or IL-21 receptor expression did not influence Listeria clearance. Thus, Listeria manipulates immune responses through a strategy of immune evasion that involves the preferential expansion of endogenous B10 cells that regulate the magnitude and duration of both innate and cellular immune responses
Interleukin-21 receptor might be a novel therapeutic target for the treatment of rheumatoid arthritis
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the synovial inflammation of the joints. Various cells and cytokines have been identified that may contribute to RA pathology. Interleukin (IL)-21 is a proinflammatory cytokine mediating pleiotropic functions through the IL-21 receptor (IL-21R). Blockade of IL-21R may represent a hopeful therapeutic approach in RA. The aim of this study was to determine the percentage of IL-21R expressing CD4+ cells and IL-21 mRNA expression in peripheral blood of RA patients. Methods: Surface expression of IL-21R on CD4+ cells in peripheral blood of RA patients (n=32 compared to healthy control participants (n=20) was evaluated by flow cytometry. Simultaneously, mononuclear cells were taken apart from the peripheral blood of individuals on a density gradient. The expression of IL-21 mRNA was assessed by real-time polymerase chain reaction. Results: IL-21R-expressing CD4+ cells from RA patients showed a significantly higher percentage of IL-21R compared with healthy controls (p< 0.05). Moreover, real-time polymerase chain reaction showed that there was no significant difference between patients and healthy controls. Conclusion: Our results indicate higher expression of IL-21R in RA patients and suggest that targeting of the IL-21R may be a novel therapeutic idea for the treatment of RA. © 2014
Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys
IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and communityacquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly
understood. Here, we investigated the role of IL-21 in this process. When administered intratracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary
MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added.
Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils.
Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was
blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This
correlated with increased type I interferon and an IFN-related gene signature, and indeed antiIFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNb
induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These
results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRS
BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers.
T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8(+) T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs
- …