Abstract
The vitamin A metabolite retinoic acid (RA) has potent immunomodulatory properties that affect T cell differentiation, migration and function. However, the precise role of RA metabolism in T cells remains unclear. Catabolism of RA is mediated by the Cyp26 family of cytochrome P450 oxidases. We examined the role of Cyp26b1, the T cell-specific family member, in CD4+ T cells. Mice with a conditional knockout of Cyp26b1 in T cells (Cyp26b1 −/− mice) displayed normal lymphoid development but showed an increased sensitivity to serum retinoids, which led to increased differentiation under both inducible regulatory T (iTreg) cell- and TH17 cell-polarizing conditions in vitro. Further, Cyp26b1 expression was differentially regulated in iTreg and TH17 cells. Transfer of naïve Cyp26b1 −/− CD4+ T cells into Rag1 −/− mice resulted in significantly reduced disease in a model of T cell-dependent colitis. Our results show that T cell-specific expression of Cyp26b1 is required for the development of T cell-mediated colitis and may be applicable to the development of therapeutics that target Cyp26b1 for the treatment of inflammatory bowel disease.
Highlights
Retinoic acid (RA) is a vitamin A metabolite that plays a critical role during embryonic development [1] and has important immunomodulatory functions in adults [2]
RA signaling in T cells has been shown to be regulated by Cyp26b1 [10]
It is known that RA signaling is not required for normal hematopoiesis but can regulate precursors of the myeloid compartment [21]
Summary
Retinoic acid (RA) is a vitamin A metabolite that plays a critical role during embryonic development [1] and has important immunomodulatory functions in adults [2]. Synthesis of RA from vitamin A is a tightly controlled process that enables specialized cells such as dendritic cells (DCs) to modulate the activation, gut homing ability and function of CD4+ T cells [5]. RA has been shown to strongly promote the differentiation of inducible regulatory T cells (iTreg cells) in the presence of TGF-b [6] and can modulate the migration and function of T helper 17 (TH17) cells in the intestine [7]. It has recently been shown that RA signaling occurs in T cells during the early stages of inflammation [8], suggesting that RA may be required for optimal effector T cell responses. Optimal TH1 effector T cell responses during Toxoplasma gondii infection require RA signaling [9]. RA signaling is critical for both effector and regulatory T cell function
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