The molecular mechanisms that regulate expression of the immunosuppressive cytokine IL-10 remain poorly understood. In this study, by measuring sensitivity to DNase I digestion, we show that ...production of IL-10 by primary mouse bone marrow-derived macrophages stimulated through pattern recognition receptors was associated with chromatin remodeling of the IL-10 locus. We also demonstrate that the IL-10 locus is remodeled in primary Th2 cells and IL-10-producing regulatory T cells that have been differentiated in vitro. Strikingly, a novel DNase I-hypersensitive site (HSS-4.5) was identified in stimulated macrophages, but not in T cells. We show that hyperacetylated histones were recruited to this site in stimulated macrophages. Furthermore, HSS-4.5 is highly conserved and contains a putative NF-kappaB binding site. In support of a function for this site, NF-kappaB p65/RelA was recruited to HSS-4.5 in vivo and its activation was required for optimal IL-10 gene expression in LPS-stimulated macrophages.
T-cell subsets in autoimmunity O'Garra, A; Murphy, K
Current opinion in immunology,
12/1993, Letnik:
5, Številka:
6
Journal Article
Recenzirano
Although differential cytokine production has been best characterized in CD4+ T cells, it is becoming clear that CD8+ T cells may also be heterogeneous at the level of cytokine production, and that ...this determines whether they exhibit inflammatory- or suppressor-type properties. Compelling evidence has accumulated in the past few years that cytokines such as interleukin-4, interleukin-10 and transforming growth factor-beta may serve as regulators of cell-mediated immunopathologies by inhibiting the development or effector function of inflammatory T cells that produce cytokines such as interferon-gamma or lymphotoxin.
The capacity of splenic CD11c+ dendritic cell (DC) populations to present antigen (Ag) to T cells differs during malarial infection with Plasmodium chabaudi in mice. Both CD11c+ CD8+ and CD8- DCs ...presented malarial peptides on their surface during infection. However, although both DC subsets expressing malaria peptides could induce interferon-gamma production by CD4 T cells, only CD8- DCs isolated at the acute phase of infection stimulated Ag-specific T cell proliferation and interleukin (IL)-4 and -10 production from MSP1-specific T cell receptor for Ag transgenic T cells coincidental with our reported Th1 to Th2 switch at this stage in response to the pathogen. The timing of these distinct DC responses coincided with increased levels of apoptosis in the CD8+ population and an increase in the numbers of CD8- DCs in the spleen. Our data suggest that the switch in CD4 T cell responses observed in P. chabaudi-infected mice may be the result of the presentation by different DC populations modified by the malaria infection.
Activation of the TPL2-MKK1/2-ERK1/2 signalling pathway is essential for lipopolysaccharide (LPS)-stimulated production of TNFα in macrophages. Here, we demonstrate that, unexpectedly, TPL2-deficient ...or MKK1-inhibited macrophages produce near normal levels of pre-TNFα when TLR2, TLR4 and TLR6 are activated by their respective agonists, but fail to secrete TNFα. We show that LPS stimulates the appearance of pre-TNFα at the cell surface and that this is prevented by inhibition of MAPK kinases 1 and 2 (MKK1/2) or in TPL2-deficient macrophages. However, the transport of pre-TNFα from the Golgi to the plasma membrane is unaffected by inhibition of the TPL2-MKK1/2-ERK1/2 pathway. Finally, we show that TACE, the protease that cleaves pre-TNFα to secreted TNFα, is phosphorylated by ERK1 and ERK2 (ERK1/2) at Thr735 in LPS-stimulated macrophages. Therefore, although TACE activity per se is not required for the LPS-stimulated cell surface expression of pre-TNFα, the phosphorylation of this protease might contribute to, or be required for, the cell surface expression of the pre-TNFα-TACE complex.
We identified functionally polarized subsets of CD4 memory T cells on the basis of the expression of CD11a, CD45RA and CD62L. Within the several phenotypically distinct subsets of CD4 memory cells ...are two that, upon stimulation, produce primarily IL-4 (MT2, CD45RA–CD62L+CD11adim) or primarily IFN-γ (MT1, CD45RA–CD62L–CD11abright). In addition, four other phenotypically distinct subsets of CD4 cells have unique cytokine profiles. To determine the clinical relevance of the representation of these cell types, we analyzed blood from patients with the chronic diseases leprosy and atopy. These diseases are characterized as immunologically polarized, since T cell responses in affected individuals are often strongly biased towards Th1 (dominated by IFN-γ production) or Th2 (IL-4 production). We show here that this polarization reflects homeostatic or differentiation mechanisms affecting the representation of the functionally distinct subsets of memory CD4 T cells, MT1 and MT2. Significantly, the representation of the MT1 and MT2 subsets differs dramatically between subjects with tuberculoid leprosy (a Th1 disease), or lepromatous leprosy or atopic disease (Th2 diseases). However, there was no difference in the cytokine profiles of these or any of the other finely resolved CD4 subsets, when compared between individuals across all disease states. Thus, it is the representation of these subsets in peripheral blood that is diagnostic of the polarized state of the immune system.
Results of a study suggest that early regulation of interleukin-4 and interleukin-10 in a developing immune response and the identity of the initiating antigen-presenting cells are critical in ...determining the Th phenotype of the developing T cells.
INTERLEUKIN-10 AND THE INTERLEUKIN-10 RECEPTOR Moore, Kevin W; de Waal Malefyt, Rene; Coffman, Robert L ...
Annual review of immunology,
01/2001, Letnik:
19, Številka:
1
Journal Article
Recenzirano
Interleukin-10 (IL-10), first recognized for its ability to inhibit
activation and effector function of T cells, monocytes, and macrophages, is a
multifunctional cytokine with diverse effects on most ...hemopoietic cell types.
The principal routine function of IL-10 appears to be to limit and ultimately
terminate inflammatory responses. In addition to these activities, IL-10
regulates growth and/or differentiation of B cells, NK cells, cytotoxic and
helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and
endothelial cells. IL-10 plays a key role in differentiation and function of a
newly appreciated type of T cell, the T regulatory cell, which may figure
prominently in control of immune responses and tolerance in vivo. Uniquely
among hemopoietic cytokines, IL-10 has closely related homologs in several
virus genomes, which testify to its crucial role in regulating immune and
inflammatory responses. This review highlights findings that have advanced our
understanding of IL-10 and its receptor, as well as its in vivo function in
health and disease.
Induction and maintenance of peripheral tolerance are important mechanisms to maintain the balance of the immune system. In addition to the deletion of T cells and their failure to respond in certain ...circumstances, active suppression mediated by T cells or T-cell factors has been proposed as a mechanism for maintaining peripheral tolerance. However, the inability to isolate and clone regulatory T cells involved in antigen-specific inhibition of immune responses has made it difficult to understand the mechanisms underlying such active suppression. Here we show that chronic activation of both human and murine CD4+T cells in the presence of interleukin (IL)-10 gives rise to CD4+T-cell clones with low proliferative capacity, producing high levels of IL-10, low levels of IL-2 and no IL-4. These antigen-specific T-cell clones suppress the proliferation of CD4+T cells in response to antigen, and prevent colitis induced in SCID mice by pathogenic CD4+CD45RBhighsplenic T cells. Thus IL-10 drives the generation of a CD4+T-cell subset, designated T regulatory cells 1 (Tr1), which suppresses antigen-specific immune responses and actively downregulates a pathological immune response in vivo .
Murine IL-10 (cytokine synthesis inhibitory factor) inhibits cytokine production by Th1 cell clones when they are activated under conditions requiring the presence of APC. By preincubating APC with ...IL-10, we demonstrate that IL-10 acts principally on APC to inhibit IFN-gamma production by Th1 clones. Moreover, IL-10 is not active when Th1 cells are stimulated with glutaraldehyde-fixed APC, which also indicates that its action involves regulation of APC function. Furthermore, IL-10 inhibits cytokine synthesis by Th1 cells stimulated with the super-antigen Staphylococcus enterotoxin B, which does not appear to require processing. Flow microfluorimetry purified splenic or peritoneal B cells and macrophages, and B cell and macrophage cell lines can present Ag to Th1 clones. However, IL-10 acts only on sorted macrophages and the macrophage cell line to suppress IFN-gamma production by Th1 clones. IL-10 does not show this effect when B cells are used as APC. In contrast, IL-10 does not impair the ability of APC to stimulate cytokine production by Th2 cells. IL-10 does not decrease IFN-gamma-induced I-Ad levels on a macrophage cell line. Inasmuch as IL-10 also inhibits IL-2-induced IFN-gamma production by Th1 cells in an Ag-free system requiring only the presence of accessory cells, these data suggest that IL-10 may inhibit macrophage accessory cell function which is independent of TCR-class II MHC interactions.
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