IL-1β Promotes TGF-β1 and IL-2 Dependent Foxp3 Expression in Regulatory T Cells

Earlier, we have shown that GM-CSF-exposed CD8α− DCs that express low levels of pro-inflammatory cytokines IL-12 and IL-1β can induce Foxp3+ Tregs leading to suppression of autoimmunity. Here, we examined the differential effects of IL-12 and IL-1β on Foxp3 expression in T cells when activated in the presence and absence of DCs. Exogenous IL-12 abolished, but IL-1β enhanced, the ability of GM-CSF-exposed tolerogenic DCs to promote Foxp3 expression. Pre-exposure of DCs to IL-1β and IL-12 had only a modest effect on Foxp3− expressing T cells; however, T cells activated in the absence of DCs but in the presence of IL-1β or IL-12 showed highly significant increase and decrease in Foxp3+ T cell frequencies respectively suggesting direct effects of these cytokines on T cells and a role for IL-1β in promoting Foxp3 expression. Importantly, purified CD4+CD25+ cells showed a significantly higher ability to maintain Foxp3 expression when activated in the presence of IL-1β. Further analyses showed that the ability of IL-1β to maintain Foxp3 expression in CD25+ T cells was dependent on TGF-β1 and IL-2 expression in Foxp3+Tregs and CD25− effectors T cells respectively. Exposure of CD4+CD25+ T cells to IL-1β enhanced their ability to suppress effector T cell response in vitro and ongoing experimental autoimmune thyroidits in vivo. These results show that IL-1β can help enhance/maintain Tregs, which may play an important role in maintaining peripheral tolerance during inflammation to prevent and/or suppress autoimmunity

Autocrine Regulation of Pulmonary Inflammation by Effector T-Cell Derived IL-10 during Infection with Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) infection is the leading viral cause of severe lower respiratory tract illness in young infants. Clinical studies have documented that certain polymorphisms in the gene encoding the regulatory cytokine IL-10 are associated with the development of severe bronchiolitis in RSV infected infants. Here, we examined the role of IL-10 in a murine model of primary RSV infection and found that high levels of IL-10 are produced in the respiratory tract by anti-viral effector T cells at the onset of the adaptive immune response. We demonstrated that the function of the effector T cell -derived IL-10 in vivo is to limit the excess pulmonary inflammation and thereby to maintain critical lung function. We further identify a novel mechanism by which effector T cell-derived IL-10 controls excess inflammation by feedback inhibition through engagement of the IL-10 receptor on the antiviral effector T cells. Our findings suggest a potentially critical role of effector T cell-derived IL-10 in controlling disease severity in clinical RSV infection

Hypofractionated simultaneous integrated boost (IMRT-SIB) with pelvic nodal irradiation and concurrent androgen deprivation therapy for high-risk prostate cancer: results of a prospective phase II trial

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The PI3K p110δ regulates expression of CD38 on regulatory T cells.

The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in PI3K-dependent suppression, we compared the transcriptome of WT and p110δ(D910A) Tregs. Among the genes that were differentially expressed was the gene for the transmembrane cyclic ADP ribose hydrolase CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3(+)CD25(+)CD4(+) T cells originating in the thymus and on Tregs in the spleen. CD38(high) WT Tregs showed superior suppressive activity to CD38(low) Tregs, which failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38(+/-) mice were unimpaired despite lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110δ(D910A) mice can in part be explained by the failure of CD38(high) cells to develop

Immune Response to Bifidobacterium bifidum Strains Support Treg/Th17 Plasticity

In this work we analyzed the immune activation properties of different Bifidobacterium strains in order to establish their ability as inductors of specific effector (Th) or regulatory (Treg) responses. First, we determined the cytokine pattern induced by 21 Bifidobacterium strains in peripheral blood mononuclear cells (PBMCs). Results showed that four Bifidobacterium bifidum strains showed the highest production of IL-17 as well as a poor secretion of IFNγ and TNFα, suggesting a Th17 profile whereas other Bifidobacterium strains exhibited a Th1-suggestive profile. Given the key role of Th17 subsets in mucosal defence, strains suggestive of Th17 responses and the putative Th1 Bifidobacterium breve BM12/11 were selected to stimulate dendritic cells (DC) to further determine their capability to induce the differentiation of naïve CD4+ lymphocytes toward different Th or Treg cells. All selected strains were able to induce phenotypic DC maturation, but showed differences in cytokine stimulation, DC treated with the putative Th17 strains displaying high IL-1β/IL-12 and low IL-12/IL-10 index, whereas BM12/11-DC exhibited the highest IL-12/IL-10 ratio. Differentiation of naïve lymphocytes confirmed Th1 polarization by BM12/11. Unexpectedly, any B. bifidum strain showed significant capability for Th17 generation, and they were able to generate functional Treg, thus suggesting differences between in vivo and vitro responses. In fact, activation of memory lymphocytes present in PBMCS with these bacteria, point out the presence in vivo of specific Th17 cells, supporting the plasticity of Treg/Th17 populations and the key role of commensal bacteria in mucosal tolerance and T cell reprogramming when needed

IL-10 from CD4+CD25−Foxp3−CD127− Adaptive Regulatory T Cells Modulates Parasite Clearance and Pathology during Malaria Infection

The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-β are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown. Here we have examined the role of natural and adaptive regulatory T cells in the control of malaria infection and find that classical CD4+CD25hi (and Foxp3+) regulatory T cells do not significantly influence the outcome of infections with the lethal (17XL) strain of Plasmodium yoelii (PyL). In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25−, Foxp3−, and CD127− and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance. In summary, we have identified a population of induced Foxp3− regulatory (Tr1) T cells, characterised by production of IL-10 and down regulation of IL-7Rα, that modulates the inflammatory response to malaria

The Molecular Signature Underlying the Thymic Migration and Maturation of TCRαβ+CD4+CD8- Thymocytes

BACKGROUND: After positive selection, the newly generated single positive (SP) thymocytes migrate to the thymic medulla, where they undergo negative selection to eliminate autoreactive T cells and functional maturation to acquire immune competence and egress capability. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the genetic program underlying this process, we analyzed changes in gene expression in four subsets of mouse TCRαβ(+)CD4(+)CD8(-) thymocytes (SP1 to SP4) representative of sequential stages in a previously defined differentiation program. A genetic signature of the migration of thymocytes was thus revealed. CCR7 and PlexinD1 are believed to be important for the medullary positioning of SP thymocytes. Intriguingly, their expression remains at low levels in the newly generated thymocytes, suggesting that the cortex-medulla migration may not occur until the SP2 stage. SP2 and SP3 cells gradually up-regulate transcripts involved in T cell functions and the Foxo1-KLF2-S1P(1) axis, but a number of immune function-associated genes are not highly expressed until cells reach the SP4 stage. Consistent with their critical role in thymic emigration, the expression of S1P(1) and CD62L are much enhanced in SP4 cells. CONCLUSIONS: These results support at the molecular level that single positive thymocytes undergo a differentiation program and further demonstrate that SP4 is the stage at which thymocytes acquire the immunocompetence and the capability of emigration from the thymus

More stories on Th17 cells

For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. the Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4(+) T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4(+) T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. the Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-beta or TGF-beta plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.Crohn's and Colitis Foundation of AmericaNIHLa Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USAUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilNIH: RO1 AI050265-06Web of Scienc

Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation

The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage, similarly to clonal deletion, is driven by intrathymic encounter of agonist self-antigens. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and those that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and -extrinsic determinants may specify the choice between these two fundamentally different T cell fates