Regulation of Th17 Differentiation by Epidermal Fatty Acid-Binding Protein

Epidermal fatty acid-binding protein, E-FABP, a lipid chaperone, has been shown to regulate the inflammatory function of macrophages and dendritic cells. Herein, we demonstrate that T cell expression of E-FABP promotes Th17 differentiation, while counterregulating development of FoxP3(+) regulatory T cells (Tregs). In response to immunization with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)), E-FABP-deficient mice generated reduced levels of Th17 cells and elevated levels of Tregs, as Compared with wild-type mice. Likewise, naive CD4(+) T cells isolated from E-FARP-deficient mice showed reduced expression of IL-17 and enhanced expression of FoxP3, in vitro, when subjected to Th17 or Treg polarizing conditions, respectively. It has been demonstrated previously that IL-21, induced by IL-6, stimulates the expression of the nuclear receptors retinoic acid-related orphan receptor (ROR)-gamma t and ROR alpha, which in turn induce expression of IL-17. We found that the impaired 1117 differentiation by E-FABP-deficient CD4(+) T cells was associated with lower levels of IL-21 expression in response to IL-6, as well as reduced expression of ROR-gamma t and ROR alpha. However, E-FABP-deficient CD4(+) T cells expressed significantly higher levels of the nuclear receptor peroxisome proliferator-activating receptor (PPAR)gamma than did wild-type CD4(+) T cells, and treatment with the PPAR gamma antagonist GW9662 restored expression of IL-21, ROR-gamma t, ROR alpha, and IL-17 by E-FABP-deficient T cells to wild-type levels. The negative influence of E-FABP deficiency on IL-17 expression was attributed to PPAR gamma-mediated suppression of IL-6-induced STAT3 activity. Thus, taken together, our data indicate that expression of E-FABP by CD4(+) T cells contributes to the control of IL-6 stimulation of the IL-21/ROR/IL-17 pathway and to the Th17/Treg counterbalance. The Journal of Immunology, 2009, 182: 7625-7633.