Regulating Treg Cells at Sites of Inflammation

Immunity (Impact Factor: 21.56). 11/2008; 29(4):511; author reply 512. DOI: 10.1016/j.immuni.2008.09.012
Source: PubMed
1 Read
  • Source
    • "Levels on CD8 T cells are substantially higher than those on Tconv cells, explaining why IL-12 more readily relieves Treg-mediated suppression of CD8 T cell proliferation. These results are consistent with previous reports showing that IL-2R is down-regulated on Tregs in inflamed tissues in the setting of infectious or autoimmune diseases and that IL-2 levels are reduced at these sites, resulting in the outgrowth of non-Treg T cells [5], [36], [37]. "
    [Show abstract] [Hide abstract]
    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 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The acquisition and execution of CD4 effector function are tightly regulated and spatially compartmentalized. In the lymph node (LN), naïve CD4+ T cells acquire specialized functions by means of expression of distinct cytokines and acquire distinct homing properties. Therefore, both the function and subsequent localization of effector cells appears to be predetermined during differentiation in the LN. Our studies with the protozoa Leishmania major suggest that this centrally (LN) generated effector repertoire can be further edited at the infected tissue site. Cytokine production in the inflamed tissue can be modulated at a number of levels including chemokine-driven differential recruitment of effector cells, the provision of signals for effector cell function and suppression by regulatory T cells (Tregs). The concept that tissue resident pathogens may subvert the centrally generated cytokine repertoire has important therapeutic implications. Novel therapies that focus on manipulating the local infection site to encourage appropriate recruitment or activation of effectors may be particularly beneficial.
    Immunologic Research 02/2009; 45(2-3):239-50. DOI:10.1007/s12026-009-8105-x · 3.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In humans and NOD mice, defects in immune tolerance result in the spontaneous development of type-1-diabetes. Recent studies have ascribed a breakdown in tolerance to dysfunction in regulatory T cells that is secondary to reduced IL-2 production by T cells having the NOD diabetes susceptibility region insulin-dependent diabetes 3 (Idd3). In this study, we demonstrate a peripheral tolerance defect in the dendritic cells of NOD mice that is independent of regulatory T cells. NOD CD8 T cells specific for islet Ags fail to undergo deletion in the pancreatic lymph nodes. Deletion was promoted by expression of the protective alleles of both Idd3 (Il2) and Idd5 in dendritic cells. We further identify a second tolerance defect that involves endogenous CD4 T cell expression of the disease-promoting NOD alleles of these genetic regions. Pervasive insulitis can be reduced by expression of the Idd3 and Idd5 protective alleles by either the Ag-presenting cell or lymphocytes.
    The Journal of Immunology 09/2009; 183(3):1533-41. DOI:10.4049/jimmunol.0900428 · 4.92 Impact Factor
Show more


1 Read
Available from