Regulating Treg Cells at Sites of Inflammation

Immunity (Impact Factor: 19.75). 11/2008; 29(4):511; author reply 512. DOI: 10.1016/j.immuni.2008.09.012
Source: PubMed
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    ABSTRACT: Complex interactions between effector T cells and Foxp3(+) regulatory T cells (Treg) contribute to clinical outcomes in cancer, and autoimmune and infectious diseases. Previous work showed that IL-12 reversed Treg-mediated suppression of CD4(+)Foxp3(-) T cell (Tconv) proliferation. We and others have also shown that Tregs express T-bet and IFN-γ at sites of Th1 inflammation and that IL-12 induces IFN-γ production by Tregs in vitro. To investigate whether loss of immunosuppression occurs when IFN-γ is expressed by Tregs we treated mouse lymphocyte cultures with IL-12. IFN-γ expression did not decrease the ability of Tregs to suppress Tconv proliferation. Rather, IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs. We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells, diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells. Together, these IL-12 mediated changes favored the outgrowth of non-Tregs. Additionally, we showed that treatment with a second cytokine, IL-27, decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation. Notably, IL-27 only slightly modified levels of IL-2R on non-Treg T cells. Together, these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-γ expression in IL-12-mediated reversal of Treg immunosuppression.
    PLoS ONE 09/2012; 7(9):e46241. DOI:10.1371/journal.pone.0046241 · 3.53 Impact Factor
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    ABSTRACT: Secretion of anti-serpinB13 autontibodies in young diabetes-prone nonobese diabetic (NOD) mice is associated with reduced inflammation in the pancreatic islets and a slower progression to autoimmune diabetes. Injection of these mice with a monoclonal antibody (mAb) against serpinB13 also leads to fewer inflammatory cells in the islets and more rapid recovery from recent-onset diabetes. An exact mechanism by which anti-serpin activity is protective remains unclear. We found that serpinB13 is expressed in the exocrine component of the mouse pancreas, including the ductal cells. We also found that anti-serpinB13 mAb blocks the inhibitory activity of serpinB13, thereby allowing partial preservation of the function of its target protease. Consistent with the hypothesis that anti-clade B serpin activity blocks the serpin from binding, exposure to exogenous anti-serpinB13 mAb or endogenous anti-serpinB13 autoantibodies resulted in the cleavage of surface molecules CD4 and CD19 in lymphocytes that accumulate in the pancreatic islets and pancreatic lymph nodes but not in the inguinal lymph nodes. This cleavage was inhibited by an E64 protease inhibitor. Consequently, T cells with the truncated form of CD4 secreted reduced levels of interferon-γ. We conclude that anti-serpin antibodies prevent serpinB13 from neutralizing proteases, thereby impairing leukocyte function and reducing the severity of autoimmune inflammation.
    Journal of Biological Chemistry 11/2012; 288(16). DOI:10.1074/jbc.M112.409664 · 4.60 Impact Factor
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    ABSTRACT: Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-γ. In this study, we have explored the molecular mechanisms underlying this NK-T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4(+) T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4(+) T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets.
    Journal of Experimental Medicine 05/2013; DOI:10.1084/jem.20122248 · 13.91 Impact Factor