Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-10

Zheng, Song Guo; Wang, Ju Hua; Gray, J. Dixon; Soucier, Harold; Horwitz, David A.

doi:10.4049/jimmunol.172.9.5213

Cited by 570 publications

(452 citation statements)

References 27 publications

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“…Our studies support the view that CD4 1 CD25 1 Treg constitute heterogeneous populations. Natural CD4 1 CD25 1 Treg have a cytokine-independent mechanism of action, but CD4 1 CD25 1 Treg induced in the periphery may have either cytokine-dependent effects or cytokine-independent effects [39]. Furthermore, SJMHE1-induced CD4 1 CD25 1 Treg had regulatory properties in vivo, i.e.…”

Section: Discussionmentioning

confidence: 98%

CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

et al. 2009

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Chronic schistosome infection results in the suppression of host immune responses, allowing long-term schistosome survival and restricting pathology. Current theories suggest that Treg play an important role in this regulation. However, the mechanism of Treg induction during schistosome infection is still unknown. The aim of this study was to determine the mechanism behind the induction of CD4 1 CD25 1 T cells by Schistosoma japonicum HSP60 (SjHSP60)-derived peptide SJMHE1 as well as to elucidate the cellular and molecular basis for the induction of CD4 1 CD25 1 T cells during S. japonicum infection. Mice immunized with SJMHE1 or spleen and LN cells from naïve mice pretreated with SJMHE1 in vitro all displayed an increase in CD4 1 CD25 1 T-cell populations. Release of IL-10 and TGF-b by SJMHE1 stimulation may contribute to suppression. Adoptively transferred SJMHE1-induced CD4 1 CD25 1 T cells inhibited delayed-type hypersensitivity in BALB/c mice. Additionally, SJMHE1-treated APC were tolerogenic and induced CD4 1 cells to differentiate into suppressive CD4 1 CD25 1 Treg. Furthermore, our data support a role for TLR2 in SJMHE1-mediated CD4 1 CD25 1 Treg induction. These findings provide the basis for a more complete understanding of the S. japonicum-host interactions that contribute to host homeostatic mechanisms, preventing an excessive immune response.Key words: CD4 1 CD25 1 Treg . Immunomodulation . Schistosomes . SJMHE1 . TLR2 Supporting Information available online IntroductionImmune regulation associated with protective immunity is intricate and entails the effective elimination of the pathogen without causing serious damage to the host. Conversely, effective pathogens have developed multiple mechanisms for modulating or suppressing host immunity as survival and dissemination strategies. Therefore, during the course of an infection, a struggle between host defense mechanisms and the pathogen's immunomodulatory processes results in a complex interplay that may result in pathogen eradication or damage to the host (and persistence of the pathogen). One of the survival strategies used by pathogens involves the induction of immunosuppressive cell populations, e.g. Treg [1,2]. 3052The first observations suggesting that Treg induction occurs during infections with certain pathogens were made in mice infected with Bordetella pertussis [3] and in humans infected with HCV [4] or the nematode Onchocerca volvulus [5]. More recently, Treg induction has been described in chronic infections caused by Candida albicans [6], Mycobacterium tuberculosis [7], HIV [8], Leishmania major [9], Litomosoides sigmodontis [10], and Helicobacter pylori [11]. Treg induction has also been associated with Schistosome infection. Schistosomiasis is a major human disease primarily caused by one of the three species of Schistosome endemic to parts of Asia, South America, and Africa, i.e. S. mansoni, S. haematobium, and S. japonicum. Mortality rates resulting from these types of parasitic infections are second only to malaria. Chronic schis...

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Section: Discussionmentioning

confidence: 98%

CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

et al. 2009

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“…Apart from the cellular-mediated dialog conferring suppressive capacity to a lymphoid population, the infectious tolerance might be mediated directly by the secretion of suppressive cytokines as TGF-b and IL-10 [2e4, 34,39]. TGF-b plays a key role in maintaining the balance between immunoprotection mediated by T cells and immunopathology either in experimental models of malaria and toxoplasma infection and in human diseases [5,29,30].…”

Section: Discussionmentioning

confidence: 99%

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

Clemente

Severini

Castronovo

et al. 2014

Microbes and Infection

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Interference with transforming growth factor-b-mediated pathways helps several parasites to survive for long periods in immunocompetent hosts. Macrophages and dendritic cells infected by Toxoplasma, Leishmania and Plasmodium spp. produce large amounts of transforming growth factor-b and induce the differentiation of antigen-specific T-regulatory cells. Mechanisms not mediated by antigen-presentation could also account for the expansion of T-regulatory cells in parasitic diseases and they also might be mediated through transforming growth factor-breceptor activated pathways. We explored the properties of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites, Trichinella spiralis muscle larvae to expand the pool of T-regulatory cells in a population of polyclonally activated T cells in the absence of accessory cells, and compared their effects to those induced by Plasmodium falciparum extracts. Similarly to P. falciparum, L. infantum extracts activate the latent soluble form of transforming growth factor-b and that bound to the membrane of activated T lymphocytes. The interaction of the active cytokine with transforming growth factor-b receptor induces Foxp3 expression by activated lymphocytes, favoring their conversion through the T-regulatory phenotype. Both Toxoplasma gondii and L. infantum extracts are able to induce transforming growth factor-b production by activated T cells in the absence of accessory cells.

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“…The follicular group was defined as the population of Foxp3 þ cells that mainly occupied lymphoid follicles of the submucosal layer compared to any other region of the tumour (original magnification: Â 4, Â 40). (Zheng et al, 2004;Fontenot et al, 2005;Allan et al, 2007;Pillai et al, 2007). Recently, it has been reported that Foxp3, forkhead/winged helix transcription factor, is the most reliable marker of T regs Yagi et al, 2004;Fontenot et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

et al. 2007

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It has been reported that the population of regulatory T cells (T regs) is increased in tumour-infiltrating lymphocytes in cancer-bearing hosts. Recently, forkhead/winged helix transcription factor p3, Foxp3, is thought to be the most reliable marker of T regs. In the present study, we investigated the prevalence and localisation pattern of Foxp3 þ cells in gastric cancer (n ¼ 80) by immunohistochemistry, in relation to the clinical outcome of gastric cancer patients. Immunohistochemical staining was performed with anti-Foxp3 mAb, and Foxp3 þ cells were semiquantified. We divided all cases into two groups: Foxp3 þ -high (n ¼ 40) and Foxp3 þ -low (n ¼ 40) groups, by the median size of the population of Foxp3 þ cells. Furthermore, in terms of the localisation pattern of accumulating Foxp3 þ cells in tumours, we classified all cases into three groups: a peri-tumour group (n ¼ 30), a diffuse group (n ¼ 40), and a follicular group (n ¼ 10). As a result, although the populations of Foxp3 þ cells in stage IV were significantly larger than those in stage I (Po0.05), there was no significant difference in survival between the patients with high and low population levels of Foxp3 þ cells. However, survival in patients with a diffuse pattern of Foxp3 þ cells was significantly poorer than in those with a peritumoral pattern. In conclusion, the localisation pattern, but not the population size, of Foxp3 þ cells was significantly related to patient survival.

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Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-10

Cited by 570 publications

References 27 publications

CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

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Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-10

Cited by 570 publications

References 27 publications

CD4+CD25+ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

CD4+CD25+ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

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CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

CD4⁺CD25⁺ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent