Kryczek I, Wei S, Zou L et al.Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 177:40-44

Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
The Journal of Immunology (Impact Factor: 5.36). 08/2006; 177(1):40-4. DOI: 10.4049/jimmunol.177.1.40
Source: PubMed

ABSTRACT Multiple modes of suppressive mechanisms including IL-10 are thought to be implicated in CD4+CD25+ regulatory T (Treg) cell-mediated suppression. However, the cellular source, role, and molecular mechanism of IL-10 in Treg cell biology remain controversial. We now studied the interaction between Treg cells and APCs. We demonstrate that Treg cells, but not conventional T cells, trigger high levels of IL-10 production by APCs, stimulate APC B7-H4 expression, and render APCs immunosuppressive. Initial blockade of B7-H4 reduces the suppressive activity mediated by Treg cell-conditioned APCs. Further, APC-derived, rather than Treg cell-derived, IL-10 is responsible for APC B7-H4 induction. Therefore, Treg cells convey suppressive activity to APCs by stimulating B7-H4 expression through IL-10. Altogether, our data provide a novel cellular and molecular mechanism for Treg cell-mediated immunosuppression at the level of APCs, and suggest a plausible mechanism for the suppressive effect of IL-10 in Treg cell-mediated suppression.

Download full-text


Available from: Huanbin Xu, Aug 13, 2015
  • Source
    • "Recently, T reg cells have also been shown to trigger high levels of IL-10 production by APCs and in turn stimulate B7-H4 expression in an autocrine fashion and render these APCs immunosuppressive (Kryczek et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral immune tolerance requires a controlled balance between the maintenance of self-tolerance and the capacity to engage protective immune responses against pathogens. Dendritic cells (DCs) serve as sentinels of the immune system by sensing environmental and inflammatory signals, and play an essential role in the maintenance of immune tolerance. To achieve this, DC play a key role in dictating the outcome of immune responses by influencing the balance between inflammatory or Foxp3(+) regulatory T (T(reg)) cell responses. At the heart of this immunological balance is a finely regulated DC and T(reg) cell crosstalk whereby T(reg) cells modulate DC phenotype and function, and DC drive the differentiation of Foxp3(+) T(reg) cells in order to control immune responses. This review will focus on recent advances, which highlight the importance of this bidirectional DC and T(reg) cell crosstalk during the induction of tolerance and organ-specific autoimmunity. More specifically, we will discuss how T(reg) cells modulate DC function for the suppression of inflammatory responses and how DC subsets employ diverse mechanisms to drive differentiation of T(reg) cells. Finally, we will discuss the therapeutic potential of tolerogenic DCs for the induction of tolerance in autoimmune diseases.
    Frontiers in Immunology 06/2012; 3:165. DOI:10.3389/fimmu.2012.00165
  • Source
    • "On the other hand, the DC-differentiation cytokines, granulocyte/macrophage colony-stimulating factor (GM-CSF) and IL-4, decrease the expression of B7-H4 in these cells [9] [10] [11]. However, interferons (INFs) appear to have minimal effects on the induction of B7-H4 expression [9] [10] [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: B7-H4 is one of the most recently identified members of B7 superfamily of costimulatory molecules serving as an inhibitory modulator of T-cell response. B7-H4 is broadly expressed in human peripheral tissues and inducibly expressed in immune cells. The expression of B7-H4 has been observed in various types of human cancer tissues, and its soluble form has been detected in blood samples from cancer patients. However, its precise physiological role is still elusive, as its receptor has not been identified and the expression levels are not consistent. This paper summarizes the pertinent data on the inhibitory role of B7-H4 in antitumor immunity and its association with cancer progression and survival in human patients. The paper also discusses the clinical significance of investigating B7-H4 as potential markers for cancer diagnosis and prognosis, and as therapeutic targets.
    Clinical and Developmental Immunology 10/2011; 2011(1740-2522):695834. DOI:10.1155/2011/695834 · 2.93 Impact Factor
  • Source
    • "This data indicates that the CD11b + IL-10-producing cells in the ascites are comprised of a myeloid population distinct from granulocytes , with phenotypic markers of monocytes, macrophages, and dendritic cells. T regulatory cells (T reg ), another suppressive population known to produce IL-10 in cancer (Liyanage et al., 2002; Marshall et al., 2004; Kawaida et al., 2005; Kryczek et al., 2006a; Mougiakakos et al., 2010), were comparatively assessed with the use of MAFIA/FOXP3-GFP mice in which both the CD115 + and FOXP3 + cells express GFP. MDSCs were identified as CD115-GFP + CD11b + cells, and T reg were identified as CD45 + CD4 + FOXP3-GFP + cells within the ascites. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Elevated levels of IL-10 in the microenvironment of human ovarian cancer and murine models of ovarian cancer are well established and correlate with poor clinical prognosis. However, amongst a myriad of immunosuppressive factors, the actual contribution of IL-10 to the ovarian tumor microenvironment, the mechanisms by which it acts, and its possible functional redundancy are unknown. We previously demonstrated that elimination of the myeloid-derived suppressor cell (MDSC) compartment within the ovarian tumor ascites inhibited tumor progression and, intriguingly, significantly decreased local IL-10 levels. Here we identify a novel pathway in which the tumor-infiltrating MDSC are the predominant producers of IL-10 and, importantly, require it to develop their immunosuppressive function in vivo. Importantly, we demonstrate that the role of IL-10 is critical, and not redundant with other immunosuppressive molecules, to in vivo tumor progression: blockade of the IL-10 signaling network results in alleviation of MDSC-mediated immunosuppression, altered T cell phenotype and activity, and improved survival. These studies define IL-10 as a fundamental modulator of both MDSC and T cells within the ovarian tumor microenvironment. Importantly, IL-10 signaling is shown to be necessary to the development and maintenance of a permissive tumor microenvironment and represents a viable target for anti-tumor strategies.
    Frontiers in Immunology 07/2011; 2:29. DOI:10.3389/fimmu.2011.00029
Show more

Similar Publications