Inflammatory T helper 1 (T(H)1)-cell responses successfully eradicate pathogens, but often also cause immunopathology. To minimize this deleterious side-effect the anti-inflammatory cytokine interleukin-10 (IL-10) is produced. Although IL-10 was originally isolated from T(H)2 cells it is now known to be produced by many cell types. Here, we discuss the recent evidence that shows that T(H)1 cells are the main source of IL-10 that controls the immune response against Leishmania major and Toxoplasma gondii infection.
"Particularly, IL-10 is a major anti-inflammatory cytokine that prevents autoimmune and inflammatory diseases
[1,2]. Additionally, IL-10 has been shown to be a feedback regulator of Th1, Th2, and allergenic immune responses
[3,4]. This cytokine is produced by different immune cell types, including B cells, macrophages, mast cells, neutrophils, dendritic cells (DC), and several T cell subsets (including Th1, Th17, Foxp3+ Tregs, and regulatory type 1 cells Tr1)
[Show abstract][Hide abstract] ABSTRACT: Studies into the regulation of interleukin-10 (IL-10), have focused only on the molecular or single-cell level. The cues that induce IL-10 in the context of cell-to-cell communication are scarce. To fill this gap, this study elucidates the cell-to-cell interaction dependent regulation of IL-10.
The simultaneous activation of CD4+ T cells via CD3/CD28 and stimulation of macrophages via CpG and their intercellular communication with each other in the same microenvironment is necessary to induce a synergistic expression of IL-10. NF-kappaB1, ERK, and STAT3 are positive regulators of this cell-to-cell communication mediated molecular change of IL-10 induction. Strikingly, the activation of CD40/CD154 signaling is a negative regulator of IL-10 levels by CD3/CD28/CpG.
These findings are of prominence as CD3/CD28/CpG treatment can induce the anti-inflammatory cytokines IL-10 and IL-30, and the activation or inhibition of the CD40/CD154 acts as molecular rheostat of the expression of IL-10 or IL-30. More importantly, this not only serves as an example of IL-10 regulation at the cellular via coordination of two signals from two cell types, but these findings also lay the molecular and cellular groundwork for future studies to investigate how to manipulate IL-10 or IL-30 production during inflammation, cancer, or autoimmune diseases.
Cell Communication and Signaling 12/2013; 11(1):95. DOI:10.1186/1478-811X-11-95 · 3.38 Impact Factor
"This finding was particularly notable as this CD4 T cell subset has previously been observed in populations living in malaria endemic areas after polyclonal stimulation with mitogen  or malaria-Ag specific activation of T cells , and we have shown that IL-10 production by IFNγ secreting CD4 T cells is a critical component of protection against severe malaria immunopathology in the mouse model of P. chabaudi infection . All together, these results suggest that malaria endemic exposure, among other infections , may drive the expansion of this specific population of IFNγ+/IL-10+ CD4 T cells and this should be addressed in a larger study. By contrast, the relative frequency of IFNγ single expressing CD4 T cells was inversely correlated with the level of malaria exposure, estimated by exposure indexes (Spearman r = −0.47, "
[Show abstract][Hide abstract] ABSTRACT: Multiparameter flow cytometry has revealed extensive phenotypic and functional heterogeneity of CD4 T cell responses in mice and humans, emphasizing the importance of assessing multiple aspects of the immune response in correlation with infection or vaccination outcome. The aim of this study was to establish and validate reliable and feasible flow cytometry assays, which will allow us to characterize CD4 T cell population in humans in field studies more fully.
We developed polychromatic flow cytometry antibody panels for immunophenotyping the major CD4 T cell subsets as well as broadly characterizing the functional profiles of the CD4 T cells in peripheral blood. We then validated these assays by conducting a pilot study comparing CD4 T cell responses in distinct populations of healthy adults living in either rural or urban Kenya. This study revealed that the expression profile of CD4 T cell activation and memory markers differed significantly between African and European donors but was similar amongst African individuals from either rural or urban areas. Adults from rural Kenya had, however, higher frequencies and greater polyfunctionality among cytokine producing CD4 T cells compared to both urban populations, particularly for "Th1" type of response. Finally, endemic exposure to malaria in rural Kenya may have influenced the expansion of few discrete CD4 T cell populations with specific functional signatures.
These findings suggest that environmentally driven T cell activation does not drive the dysfunction of CD4 T cells but is rather associated with greater magnitude and quality of CD4 T cell response, indicating that the level or type of microbial exposure and antigenic experience may influence and shape the functionality of CD4 T cell compartment. Our data confirm that it is possible and mandatory to assess multiple functional attributes of CD4 T cell response in the context of infection.
PLoS ONE 01/2013; 8(1):e55195. DOI:10.1371/journal.pone.0055195 · 3.23 Impact Factor
"The secretion of IL-10 by CD4+FoxP3+ cells is considered to be one of the most important mechanisms via which this cell subpopulation exerts the immunosuppressive function [30, 31, 31]. IL-10 is an anti-inflammatory cytokine which inhibits the secretion of proinflammatory cytokines by the macrophages and dendritic cells . It inhibits the activities of Th17  and the differentiation of blood monocytes into dendritic cells [11, 30]. "
[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cells (MSCs) are a new and promising tool for therapy of autoimmune disorders. In recent years their possibility to take part in the modulation of the immune response is discussed. The exact mechanisms for immunoregulation realized by MSCs are not clear yet, but interactions with other immunoregulatory cells may be involved in this process. The investigation of the influence of MSCs on the expression of FoxP3 and cytokine secretion by T helper cells was the aim of this study. T helper cells were isolated from PBMCs by magnetic separation and MSCs were isolated from human adipose tissue, and CD4+ T cells were cultured with conditional medium of MSCs. The methods which were used include flow cytometry, ELISA, and Human Proteome profiler kits. The results demonstrated that secretory factors in MSCs conditional medium lead to increased expression of FoxP3 and increased secretion of IL-10 by T helpers. The obtained results give us opportunity to discuss the interaction between two kinds of immunoregulatory cells: MSCs and FoxP3+ T helpers. We suppose that this interaction leads to increased number of immunosuppressive helpers which secrete IL-10. MSCs provide some of their immunosuppressive functions acting on T regulatory cells, and we believe that IL-6 secreted by MSCs is involved in this process.
BioMed Research International 11/2012; 2012(1):295167. DOI:10.1155/2012/295167 · 2.71 Impact Factor
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