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Retinoic acid signalling is required for the pathogenicity of effector CD4+ T cells during the development of intestinal inflammation

This paper was not found in any repository; the policy of its publisher is unknown or unclear.
This paper was not found in any repository; the policy of its publisher is unknown or unclear.

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Abstract

The vitamin A metabolite retinoic acid (RA) seems to be a double-edge sword in CD4+ T cell biology, sustaining the development of foxp3+ Treg cells, but also being essential for the stability of the Th1 lineage. Here we explored the role of RA signalling in CD4+ T cells during the development of intestinal inflammation in the T cell transfer colitis model. RA signalling-deficient CD4+ T cells are less potent at inducing intestinal inflammation compared to their RA signalling-proficient counterparts and exhibit a differentiation skewing towards more IL-17+ and foxp3+ cells, while their capacity to differentiate into Th1 cells is compromised. In vitro studies confirm the inefficacy of RA signalling-deficient T cells to generate bona fide Th1 cells and demonstrate their aberrant increased RORγt expression, while their Th17 differentiation remains unaffected. Surprisingly, RA signalling-deficient and –proficient Tregs are equally competent to inhibit colitis development. Together our results indicate that RA, through its receptor RARα, negatively regulates the early expansion of CD4+ T cells during colitis and is necessary for the generation of colitogenic Th1/Th17 cells, while it is dispensable for the protective function of Treg cells. We are currently deciphering the mechanisms of these effects of RA on CD4+ T cells.