Autoimmune-mediated intestinal inflammation-impact and regulation of antigen-specific CD8+ T cells.
ABSTRACT Few data exist regarding mechanisms of mucosal CD8+ T-cell reactivity to epithelial-specific antigen. To dissect the immunologic mechanisms underlying CD8+ T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocompatibility complex class I-restricted T-cell receptor specific for this antigen was studied. In addition, antigen-specific regulatory CD4+ T cells induced in vivo were tested to control these autoreactive CD8+ T cells.
Transgenic VILLIN-HA mice were mated with CL4-TCR transgenic mice. Alternatively, adoptive transfer of CL4-TCR transgenic CD8+ T cells into VILLIN-HA transgenic mice was performed to mimic spontaneous encounter of neoantigen. Mucosal CD8+ T cells were characterized under different conditions of tolerance, immunopathology, and active immunosuppression.
Transgenic CD8+ T cells from VILLIN-HA x CL4-TCR transgenic mice preferentially migrated and expanded in mucosal lymphoid tissues. Although transgenic CD8+ T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4+ and CD8+, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8+ T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8+ T cells secreted vigorous amounts of proinflammatory cytokines like interferon gamma/tumor necrosis factor alpha. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4+ T cells.
Epithelial-specific antigen expression is sufficient to trigger severe antigen-specific CD8+ T-cell-mediated intestinal inflammation; this might be controlled by antigen-specific regulatory T cells under physiological conditions.
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ABSTRACT: Background Endometrial regenerative cells (ERCs) are mesenchymal-like stem cells that can be non-invasively obtained from menstrual blood and are easily grown /generated at a large scale without tumorigenesis. We previously reported that ERCs exhibit unique immunoregulatory properties in vitro, however their immunosuppressive potential in protecting the colon from colitis has not been investigated. The present study was undertaken to determine the efficacy of ERCs in mediating immunomodulatory functions against colitis.Methods Colitis was induced by 4% dextran-sulfate-sodium (DSS, in drinking water) in BALB/c mice for 7 days. ERCs were cultured from healthy female menstrual blood, and injected (1 million/mouse/day, i.v.) into mice on days 2, 5, and 8 following colitis induction. Colonic and splenic tissues were collected on day 14 post-DSS-induction. Clinical signs, disease activity index (DAI), pathological and immunohistological changes, cytokine profiles and cell populations were evaluated.ResultsDSS-induced mice in untreated group developed severe colitis, characterized by body-weight loss, bloody stool, diarrhea, mucosal ulceration and colon shortening, as well as pathological changes of intra-colon cell infiltrations of neutrophils and Mac-1 positive cells. Notably, ERCs attenuated colitis with significantly reduced DAI, decreased levels of intra-colon IL-2 and TNF-¿, but increased expressions of IL-4 and IL-10. Compared with those of untreated colitis mice, splenic dendritic cells isolated from ERC-treated mice exhibited significantly decreased MHC-II expression. ERC-treated mice also demonstrated much less CD3+CD25+ active T cell and CD3+CD8+ T cell population and significantly higher level of CD4+CD25+Foxp3+ Treg cells.Conclusions This study demonstrated novel anti-inflammatory and immunosuppressive effects of ERCs in attenuating colitis in mice, and suggested that the unique features of ERCs make them a promising therapeutic tool for the treatment of ulcerative colitis.Journal of Translational Medicine 12/2014; 12(1):344. DOI:10.1186/s12967-014-0344-5 · 3.99 Impact Factor
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ABSTRACT: Regulatory T cells (Treg) are supportive to cancer development in most tissues but their role in colitis-associated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4+Foxp3+ Treg in a mouse model of CAC and in colon cancer patients. These Treg were increased strongly in number in a mouse model of CAC and in the peripheral blood of colon cancer patients, exhibiting an activated phenotype as defined by elevated expression of GARP, CD103, CTLA-4 and IL-10, along with an increased suppressive effect on the proliferation and Th1 cytokine expression of CD4+CD25- responder T cells ex vivo. Transient ablation of CD4+Foxp3+ regulatory T during tumor development in the CAC model suppressed tumor outgrowth and distribution, accompanied by an increased number of CD8+IFN-γ-/granzyme B-producing effector T cells. Conversely, inactivation of IL-10 in Treg did not elevate the antitumor response but instead further boosted tumor development. Our results establish a tumor-promoting function for Treg during CAC formation, but they also suggest that a selective, transient ablation of Treg can evoke antitumor responses, with implications for immunotherapeutic interventions in CAC patients.Cancer Research 06/2014; 74(16). DOI:10.1158/0008-5472.CAN-13-3065 · 9.28 Impact Factor
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ABSTRACT: We found the first evidence of the efficacy of a herbal treatment with myrrh, dry extract of chamomile flowers, and coffee charcoal for ulcerative colitis (UC). However, the impact of the herbal treatment on the CD4+ T-cell compartment, which is essential for both the induction of UC and the maintenance of tolerance in the gut, is not well understood.PLoS ONE 08/2014; 9(8):e104257. DOI:10.1371/journal.pone.0104257 · 3.53 Impact Factor