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: 4.92). 08/2006; 177(1):40-4. DOI: 10.4049/jimmunol.177.1.40
Source: PubMed


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.

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Available from: Huanbin Xu, Aug 13, 2015
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    • "Furthermore, Tregs may convert APCs to become themselves immunosuppressive (78). It has also been proposed that Tregs act by competing with other cells for growth factors, particularly IL-2 (79, 80). "
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    ABSTRACT: To maintain immunological balance the organism has to be tolerant to self while remaining competent to mount an effective immune response against third-party antigens. An important mechanism of this immune regulation involves the action of regulatory T-cell (Tregs). In this mini-review, we discuss some of the known and proposed mechanisms by which Tregs exert their influence in the context of immune regulation, and the contribution of mathematical modeling for these mechanistic studies. These models explore the mechanisms of action of regulatory T cells, and include hypotheses of multiple signals, delivered through simultaneous antigen-presenting cell (APC) conjugation; interaction of feedback loops between APC, Tregs, and effector cells; or production of specific cytokines that act on effector cells. As the field matures, and competing models are winnowed out, it is likely that we will be able to quantify how tolerance-inducing strategies, such as CD4-blockade, affect T-cell dynamics and what mechanisms explain the observed behavior of T-cell based tolerance.
    Frontiers in Immunology 11/2013; 4:378. DOI:10.3389/fimmu.2013.00378
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    • "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). "
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    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
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    • "These studies provide compelling evidence that over-expression of B7-H4 in tumors inhibits T-cell responses through modulation of suppressive APC. The mechanism for this inhibition on T cells by B7-H4 had been proposed to be in part through Treg-stimulated B7-H4 expression on induction of APCs [25]. However, the signaling pathways in T cells altered by B7-H4 ligation have not been well studied. "
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    ABSTRACT: B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine-secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3(+) T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR)/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK) are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL-2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK.
    PLoS ONE 01/2012; 7(1):e28232. DOI:10.1371/journal.pone.0028232 · 3.23 Impact Factor
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