Stock et al - 2004 Nature Publishing Group...

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Induction of T helper type 1–like regulatory cells that express Foxp3 and protect against airway hyper-reactivity Philippe Stock 1,4 , Omid Akbari 1,4 , Gerald Berry 2 , Gordon J Freeman 3 , Rosemarie H DeKruyff 1,4 & Dale T Umetsu 1,4 The range of regulatory T cell (T R cell) types that control immune responses is poorly understood. We describe here a population of T R cells that developed in vivo from naive CD4 + CD25 T cells during a T helper type 1 (T H 1)–polarized response, distinct from CD25 + T R cells. These antigen-specific T R cells were induced by CD8 a + DCs, produced both interleukin 10 and interferon- c , and potently inhibited the development of airway hyper-reactivity. These T R cells expressed the transcription factors Foxp3 and T-bet, indicating that these T R cells are related to T H 1 cells. Thus, adaptive T R cells are heterogeneous and comprise T H 1-like T R cells as well as previously described T H 2-like T R cells, which express Foxp3 and are induced during the development of respiratory tolerance by CD8 a DCs. There is now convincing evidence that regulatory CD4 + T cells are essential in the control of immune responses by inhibiting the function of T helper type 1 (T H 1) and T H 2 effector cells. Several distinct types of CD4 + T regulatory (T R ) cells have been described, including CD4 + CD25 + T cells, that develop naturally in the thymus, constitute 5–10% of CD4 + T cells from naive mice and provide potent inhibitory activity against autoreactive T cells (called ‘natural T R cells’) 1 . In addition, several forms of antigen-specific T R cells have been described that are induced after exposure to specific, exogenous antigen (called ‘adaptive T R cells’) 2 . These include T R 1 cells, which develop in vitro in the presence of interleukin 10 (IL-10) 3 or in the presence of vitamin D3 and dexamethasone 4 , produce IL-10 and inhibit inflammatory responses in the colon and central nervous system. Adaptive T R cells also include antigen-specific T R cells that develop in vivo from CD25 naive T cells after epicutaneous immu- nization with autoantigenic peptides and inhibit experimental allergic encephalomyelitis 5 or that develop from CD25 naive T cells after respiratory exposure to antigen and inhibit the development of allergen-induced airway hyper-reactivity (AHR) 6 . Furthermore, T H 3 cells have been described that develop after exposure to oral antigen and inhibit the development of experimental autoimmune encepha- lomyelitis 7 . However, because adaptive T R cells have been difficult to generate, isolate and study, the relationship between natural and adaptive T R cells, specific methods that efficiently induce the devel- opment of adaptive T R cells and the full range of adaptive T R cells that exist are not fully understood.
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