Editors' ChoiceImmunology

Inflamed About Retinoic Acid

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Science Signaling  15 Mar 2011:
Vol. 4, Issue 164, pp. ec75
DOI: 10.1126/scisignal.4164ec75

Gut-associated immune cells distinguish between antigens associated with pathogens and those associated with food, mounting an immune response to the former but inducing tolerance to the latter. In celiac disease, this system goes awry, so that dietary gluten triggers an inflammatory response (see Maynard and Weaver). Noting that interleukin-15 (IL-15) is abundant in the gut of individuals with celiac disease, DePaolo et al. investigated its effects on the ability of mesenteric lymph node (MLN) dendritic cells to promote T cell differentiation into regulatory T (Treg) cells. IL-15 impaired MLN dendritic cell–mediated Treg differentiation in vitro; moreover, Treg differentiation was suppressed in transgenic mice overexpressing IL-15 in the MLN and lamina propria (Dd-IL-15 transgenic mice) that ingested antigen. Surprisingly, retinoic acid (RA), which is produced by MLN dendritic cells and has been implicated in Treg differentiation, decreased Treg differentiation in antigen-fed Dd-IL-15 mice even further. A combination of in vitro and in vivo analyses revealed that IL-15 promoted dendritic cell production of the proinflammatory cytokines IL-12 and IL-23 and thereby the production of inflammatory effector T cells. RA acted synergistically with IL-15 to stimulate phosphorylation of c-Jun N-terminal kinase in dendritic cells, as well as their release of IL-12 and IL-23, and acted together with IL-12 at the T cell level to promote differentiation into inflammatory effector T cells. Susceptibility to celiac disease is associated with expression of the human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules, and Dd-IL-15 mice crossed with mice expressing human HLA-DQ8 (DQ8-Dd-IL-15 mice) fed the gluten component gliadin developed features of early-stage celiac disease, with RA promoting the induction of inflammatory antigliadin responses. Thus, in contrast to its normal role in gut, in the presence of IL-15, RA appears to promote an intestinal inflammatory response instead of tolerance.

R. W. DePaolo, V. Abadie, F. Tang, H. Fehlner-Peach, J. A. Hall, W. Wang, E. V. Marietta, D. D. Kasarda, T. A. Waldmann, J. A. Murray, C. Semrad, S. S. Kupfer, Y. Belkaid, S. Guandalini, B. Jabri, Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220–224 (2011). [PubMed]

C. L. Maynard, C. T. Weaver, Context is key in the gut. Nature 471, 169–170 (2011). [PubMed]

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