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Ulcerative colitis (UC) is a complex polygenic disease that arises in the context of as yet unknown environmental factors.1 One biological pathway that has arisen as being important to UC, but not Crohn's disease (CD), is that associated with dysregulated CD1d-restricted, natural killer T (NKT) cell responses.2–4 CD1d-restricted NKT cells are a specialised subset of T cells that recognise lipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex (MHC) class I-related molecule, on antigen-presenting cells. Upon ligation of their T cell receptor (TCR), NKT cells immediately release a large spectrum of cytokines such as interferon γ (IFNγ), interleukin 4 (IL-4), IL-13 and many others. The lipid ligands responsible for NKT cell activation in UC are however unknown, but probably include both endogenous and exogenous lipids from microbes.4
The mechanistic relationship between NKT cells and UC derives mostly from animal models and correlative human studies.2 The earliest observations on the ontogeny of these concepts was the recognition that CD1d is expressed on mouse and human intestinal epithelial cells5 6 and that CD1d on epithelial cells is functionally able to activate NKT cells.7 These studies were later followed by the discovery that NKT cells secreting IL-13 were critical for the induction of experimental colitis resembling human UC.2 Subsequent careful studies of colonic lamina propria T cells obtained from patients with UC confirmed a similar CD1d-dependent upregulation of IL-13 secretion. These studies not only …
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Funding The authors' laboratories are supported by NIH RO1 grants DK44319, DK51362, DK53056 and DK08819 (RSB), T32 DK07533-21A1 (RSB) and P30 DK034854 (Harvard Digestive Diseases Center), European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 260961 (AK), the Austrian Science Fund and Ministry of Science P21530 (AK) and START Y446 (AK), and the National Institute for Health Research Cambridge Biomedical Research Centre (AK). RSB is listed as co-inventor on a patent involving IL-13 targeting for the treatment of UC.
Competing interests None.
Provenance and peer review Commissioned; not externally peer reviewed.