We further demonstrate that CD4+CD25+Foxp3+ TREG cells readily inhibit these responses and mediate disease protection, which correlates with their accumulation in the draining LN and lamina propria. Moreover, TREG cells can directly suppress γδ T-cell expansion and cytokine production in vitro and in vivo, suggesting a pathogenic role of γδ T cells in intestinal inflammation. Thus, functional alterations in TREG cells provoke dysregulated CD4+ and γδ T-cell responses to commensal

antigens in the intestine. The gastrointestinal tract represents a major site where immune tolerance mechanisms assure a homeostatic Ensartinib research buy equilibrium between the mucosal immune system and commensal microorganisms 1, 2. Given the permanent co-existence of harmless and pathogenic bacteria that constantly trigger local immune responses, the intestinal mucosa must maintain tolerance in these sites. A disturbance in immune homeostasis of the human gut may provoke inflammatory bowel diseases (IBDs) like Crohn’s

disease (CD) and ulcerative colitis, both characterized by CHIR-99021 research buy an abnormal accumulation of activated lymphocytes in the gut resulting in chronic intestinal inflammation 1–5. CD4+Foxp3+ TREG cells are widely recognized as dominant mediators responsible for the control of peripheral tolerance 6–10. Functional abrogation of these cells results in over-activation and uncontrolled inflammatory responses towards tissue-derived antigens and commensal bacteria, leading to the development of various chronic inflammatory disorders 10–13. Our current understanding of the role of Foxp3+

TREG cells in the prevention of IBD development is largely derived from mouse models where intestinal inflammation is induced by adoptive transfer of CD4+ T effector (TEFF) cells into lymphocyte-deficient nude, selleck screening library SCID or RAG−/− hosts 14. Collectively, these studies show that CD4+Foxp3+ TREG cells prevent colitis development or even cure established disease by restraining pathogenic CD4+ T-cell and DC immune responses 15–18. However, other cellular targets of suppression in vivo remain ill-defined. Recently, increasing evidence points to a significant multi-faceted role for non-CD4+ lymphocytes, including γδ T cells, in the maintenance of intestinal homeostasis 19–21. More specifically, it has been shown that γδ T cells readily accumulate in inflamed tissues of IBD patients 22–25, although, in murine studies, γδ T cells have been shown to either potently reduce 26–28 or exacerbate inflammation 29–33. Some studies also identify γδ T cells as a source of rapidly activated T cells with Th17-like effector properties providing the first line of defense against pathogens 34–36.