Leptin favors imbalance of antigen-specific CD4(+) T-cells associated with severity of cat allergy

INTRODUCTION: Obesity can complicate IgE-mediated allergic diseases. In the present study, we aimed to investigate the ability of obesity-related concentrations of leptin to modulate the in vitro effector and regulatory Fel d1-specific CD4(+) T-cell subsets in patients allergic to cat, considered the third most common cause of respiratory allergy in humans. METHODS: For this study, plasma and peripheral blood mononuclear cells (PBMC) from 30 cat-allergic patients with mild, moderate and severe respiratory symptoms were obtained. The PBMC cultures were stimulated with Fel d1 antigen (10 µg/mL) in the presence or absence of obesity-related leptin dose (50 ηg/mL). After 6 days, the levels of cytokines and IgE in the supernatants were evaluated by multiplex and ELISA, respectively. The frequency of different non-follicular (CXCR5(-)) and follicular (CXCR5(+)) Fel d1-specific CD4(+) T cell subsets was determined by flow cytometry. The plasma levels of leptin and IgE anti-cat titers were evaluated by ELISA and ImmunoCAP, respectively. RESULTS AND CONCLUSIONS: Fel d1 induced both IgE production and release of cytokines related to Th2, Th9 and Th17 cell phenotypes. Feld1 was more efficient in increasing the frequency of T(FH)IL-21(-) cells positive for IL-4, IL-5 and IL-13 than T(FH)IL-21(+) cell subsets. Leptin favored the expansion Th2-like and Th9-like cells and T(FH)IL-21(-) cells positive for IL-4, IL-5 and IL-13, but reduced the proportion of conventional (Treg/Tr-1) and follicular (T(FR)) regulatory CD4(+) T-cell subsets expressing or not CD39 marker. Finally, many of the imbalances between Fel d1-specific CD4(+) T-cells were also correlated with plasma leptin and anti-Fel d1 IgE titers. In summary, hyperleptinemia should negatively impact on the severity of cat allergies by favoring the expansion of pathogenic Fel d1-specific CD4(+) T-cell phenotypes and damaging the functional status of regulatory CD4(+) T-cell subsets.