Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3−CD25− CD4+ Regulatory T Cells

Department of Microbiology and Immunology, University of Gothenburg, Goeteborg, Västra Götaland, Sweden
The Journal of Immunology (Impact Factor: 4.92). 01/2007; 177(11):7634-44. DOI: 10.4049/jimmunol.177.11.7634
Source: PubMed


Oral administration of Ag coupled to cholera toxin B subunit (CTB) efficiently induces peripheral immunological tolerance. We investigated the extent to which this oral tolerance is mediated by CD25+CD4+ regulatory T cells (T(reg)). We found that total T(reg), KJ1-26+ T(reg) and CTLA-4+ T(reg) were all increased in Peyer's patches, mesenteric lymph nodes, and, to a lesser extent, in spleen of mice after intragastric administration of OVA/CTB conjugate, which also increased TGF-beta in serum. This could be abolished by co-administering cholera toxin or by treatment with anti-TGF-beta mAb. CD25+ T(reg), but also CD25-CD4+ T cells from OVA/CTB-treated BALB/c or DO11.10 mice efficiently suppressed effector T cell proliferation and IL-2 production in vitro. Following adoptive transfer, both T cell populations also suppressed OVA-specific T cell and delayed-type hypersensitivity responses in vivo. Foxp3 was strongly expressed by CD25+ T(reg) from OVA/CTB-treated mice, and treatment also markedly expanded CD25+Foxp3+ T(reg). Furthermore, in Rag1(-/-) mice that had adoptively received highly purified Foxp3-CD25-CD4+ OT-II T cells OVA/CTB feeding efficiently induced CD25+ T(reg) cells, which expressed Foxp3 more strongly than naturally developing T(reg) and also had stronger ability to suppress effector OT-II T cell proliferation. A remaining CD25- T cell population, which also became suppressive in response to OVA/CTB treatment, did not express Foxp3. Our results demonstrate that oral tolerance induced by CTB-conjugated Ag is associated with increase in TGF-beta and in both the frequency and suppressive capacity of Foxp3+ and CTLA-4+ CD25+ T(reg) together with the generation of both Foxp3+ and Foxp3-CD25- CD4+ T(reg).

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    • "On the basis of murine models it has been postulated that natural Treg cells are dispensable for protein specific oral tolerance [9]. In contrast, induced Tregs that have differentiated from naive T cells in the tolerogenic environment of the gut-draining lymph nodes can mediate protein specific oral tolerance in these models [10], [11], [12], [13], [14]. Currently, it is technically impossible to study gluten-specific Treg in patients. "
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    ABSTRACT: Celiac disease (CD) is an intestinal inflammation driven by gluten-reactive CD4(+) T cells. Due to lack of selective markers it has not been determined whether defects in inducible regulatory T cell (Treg) differentiation are associated with CD. This is of importance as changes in numbers of induced Treg could be indicative of defects in mucosal tolerance development in CD. Recently, we have shown that, after encounter of retinoic acid during differentiation, circulating gut-imprinted T cells express CD62L(neg)CD38(+). Using this new phenotype, we now determined whether alterations occur in the frequency of natural CD62L(+)Foxp3(+) Treg or mucosally-imprinted CD62L(neg)CD38(+)Foxp3(+) Treg in peripheral blood of CD patients. In particular, we compared pediatric CD, aiming to select for disease at onset, with adult CD. Cell surface markers, intracellular Foxp3 and Helios were determined by flow cytometry. Foxp3 expression was also detected by immunohistochemistry in duodenal tissue of CD patients. In children, the percentages of peripheral blood CD4(+)Foxp3(+) Treg were comparable between CD patients and healthy age-matched controls. Differentiation between natural and mucosally-imprinted Treg on the basis of CD62L and CD38 did not uncover differences in Foxp3. In adult patients on gluten-free diet and in refractory CD increased percentages of circulating natural CD62L(+)Foxp3(+) Treg, but normal mucosally-imprinted CD62L(neg)CD38(+)Foxp3(+) Treg frequencies were observed. Our data exclude that significant numeric deficiency of mucosally-imprinted or natural Foxp3(+) Treg explains exuberant effector responses in CD. Changes in natural Foxp3(+) Treg occur in a subset of adult patients on a gluten-free diet and in refractory CD patients.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "Priming in the presence of TGF-β induces regulatory activity and FoxP3 expression in naïve CD4 T cells [21], and FoxP3 expression associated with suppressive activity is also inducible in both murine [22] and human γδ T cells [23]. Notably, however, regulatory activity independent of FoxP3 has also been described for CD4 T cells [24]. Moreover, type 1 regulatory (Tr1) T cells are induced via an IL-10-dependent pathway both in vitro and in vivo. "
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    ABSTRACT: γδ T cells account for approximately 5% of peripheral blood T cells but are more abundant in mucosal tissue. Based on the recognized ligands and their general lack of MHC restriction, γδ T cells are considered as unconventional T cells that link innate and adaptive immunity. γδ T cells produce a diverse range of cytokines, exert cytotoxic effector function, can act as antigen-presenting cells, and display regulatory activity. Here we review the current knowledge on the regulatory functions of murine and human γδ T cells. Some γδ T cells produce inhibitory cytokines such as transforming growth factor-β but γδ T cells can utilize additional regulatory mechanisms. By subverting regulatory T cells (Treg) through induction of Treg apoptosis or cytokine-dependent reversal of Treg activity, however, γδ T cells can also enhance effector T cell activity and thereby contribute to autoimmunity. A more precise understanding of the plasticity of regulatory γδ T cells is required to specifically identify strategies for intentional modulation of their beneficial or detrimental regulatory activity.
    Full-text · Article · Feb 2013 · International immunopharmacology
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    • "Further identification of the specific IL-10 and TGF-β producing-cells in the ex vivo experiments of this study is necessary to characterize other relevant cells as IL-10 producing-dendritic cells. Our results also agree with studies showing that oral tolerance induced by low doses of CTB antigen conjugates expands Treg cells, upregulates IL-10 and TGF-β and reduces levels of IFNγ and other Th1- associated cytokines (Sun et al., 2000; Aspord and Thivolet, 2002; Sun et al., 2006). Furthermore, we showed that oral tolerance induced by LTBSC treatment also caused a drastic reduction in Th17 response. "
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    ABSTRACT: We previously found that the preventive oral administration of a hybrid consisting of the C domain of synapsin and the B subunit of E. coli heat-labile enterotoxin (LTBSC) efficiently suppresses experimental autoimmune encephalomyelitis (EAE) development in rats. We investigated the effect of LTBSC on cytokine expression and on regulatory T (Treg) cells in rats with myelin induced EAE. LTBSC treatment increased the frequency of CD4(+)FoxP3(+) Treg cells in lymph nodes prior to challenge and in the EAE acute stage. LTBSC also up-regulated the expression of anti-inflammatory Th2/Th3 cytokines and diminished myelin basic protein-specific Th1 and Th17 cell responses in lymph nodes. CD4(+)CD25(+) Treg cells from LTBSC treated rats showed stronger suppressive properties than Treg cells from controls in vitro. Our observations indicate that LTBSC is a useful agent for modulating the autoimmune responses in EAE.
    Full-text · Article · Dec 2011 · Journal of neuroimmunology
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