Fatty acid‐binding protein 3 controls contact hypersensitivity through regulating skin dermal Vγ4+ γ/δ T cell in a murine model

Background Fatty acid‐binding protein 3 (FABP3) is a cytosolic carrier protein of polyunsaturated fatty acids (PUFAs) and regulates cellular metabolism. However, the physiological functions of FABP3 in immune cells and how FABP3 regulates inflammatory responses remain unclear. Methods Contact hypersensitivity (CHS) induced by 2,4‐dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin wild‐type and Fabp3−/− mice. Skin inflammation was assessed using FACS, histological, and qPCR analyses. The development of γ/δ T cells was evaluated by a co‐culture system with OP9/Dll1 cells in the presence or absence of transgene of FABP3. Results Fabp3‐deficient mice exhibit a more severe phenotype of contact hypersensitivity (CHS) accompanied by infiltration of IL‐17‐producing Vγ4+ γ/δ T cells that critically control skin inflammation. In Fabp3−/− mice, we found a larger proportion of Vγ4+ γ/δ T cells in the skin, even though the percentage of total γ/δ T cells did not change at steady state. Similarly, juvenile Fabp3−/− mice also contained a higher amount of Vγ4+ γ/δ T cells not only in the skin but in the thymus when compared with wild‐type mice. Furthermore, thymic double‐negative (DN) cells expressed FABP3, and FABP3 negatively regulates the development of Vγ4+ γ/δ T cells in the thymus. Conclusions These findings suggest that FABP3 functions as a negative regulator of skin inflammation through limiting pathogenic Vγ4+ γ/δ T‐cell generation in the thymus. FABP3 negatively regulates the differentiation of thymic DN2 cells into Vγ4+ γ/δ T cells. FABP3‐deficient mice exhibit higher frequency of Vγ4+ γ/δ T cells in skin of both juvenile and adults. FABP3 deficiency in Vγ4+ γ/δ T cells enhances production of high amounts of IL‐17A, which contributes to the pathogenesis of contact hypersensitivity. DN2, double negative cell; FABP3, fatty acid‐binding protein 3; KO, knockout. Abbreviations: DN2, double negative cell; FABP3, fatty acid‐binding protein 3; KO, knockout.