Microbial metabolites control the thymic development of mucosal-associated invariant T cells

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Science  25 Oct 2019:
Vol. 366, Issue 6464, pp. 494-499
DOI: 10.1126/science.aaw2719

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Commensals rule the MAITrix

Mucosal-associated invariant T (MAIT) cells play an important role in mucosal homeostasis. MAIT cells recognize microbial small molecules presented by the major histocompatibility complex class Ib molecule MR1. MAIT cells are absent in germ-free mice, and the mechanisms by which microbiota control MAIT cell development are unknown (see the Perspective by Oh and Unutmaz). Legoux et al. show that, in mice, development of MAIT cells within the thymus is governed by the bacterial product 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil, which rapidly traffics from the mucosa to the thymus, where it is captured by MR1 and presented to developing MAIT cells. Constantinides et al. report that MAIT cell induction only occurs during a limited, early-life window and requires exposure to defined microbes that produce riboflavin derivatives. Continual interactions between MAIT cells and commensals in the skin modulates tissue repair functions. Together, these papers highlight how the microbiota can direct immune cell development and subsequent function at mucosal sites by secreting compounds that act like self-antigens.

Science, this issue p. 494, p. eaax6624; see also p. 419


How the microbiota modulate immune functions remains poorly understood. Mucosal-associated invariant T (MAIT) cells are implicated in mucosal homeostasis and absent in germ-free mice. Here, we show that commensal bacteria govern murine MAIT intrathymic development, as MAIT cells did not recirculate to the thymus. MAIT development required RibD expression in bacteria, indicating that production of the MAIT antigen 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) was necessary. 5-OP-RU rapidly traveled from mucosal surfaces to the thymus, where it was captured by the major histocompatibility complex class Ib molecule MR1. This led to increased numbers of the earliest MAIT precursors and the expansion of more mature receptor-related, orphan receptor γt–positive MAIT cells. Thus, a microbiota-derived metabolite controls the development of mucosally targeted T cells in a process blurring the distinction between exogenous antigens and self-antigens.

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