Abstract: Pomegranate peel extract (PoPEx) has been shown to have antioxidant and anti-inflammatory
properties, but its effect on the adaptive immune system has not been sufficiently investigated. In
this study, the treatment of human peripheral blood mononuclear cells (PBMC) with PoPEx (range
6.25–400 µg/mL) resulted in cytotoxicity at concentrations of 100 µg/mL and higher, due to the
induction of apoptosis and oxidative stress, whereas autophagy was reduced. At non-cytotoxic concentrations, the opposite effect on these processes was observed simultaneously with the inhibition
of PHA-induced PBMC proliferation and a significant decrease in the expression of CD4. PoPEx
differently modulated the expression of activation markers (CD69, CD25, ICOS) and PD1 (inhibitory
marker), depending on the dose and T-cell subsets. PoPEx (starting from 12.5 µg/mL) suppressed
the production of Th1 (IFN-γ), Th17 (IL-17A, IL-17F, and IL-22), Th9 (IL-9), and proinflammatory
cytokines (TNF-α and IL-6) in culture supernatants. Lower concentrations upregulated Th2 (IL-5
and IL-13) and Treg (IL-10) responses as well as CD4+CD25hiFoxp3+ cell frequency. Higher concentrations of PoPEx increased the frequency of IL-10- and TGF-β-producing T-cells (much higher in
the CD4+ subset). In conclusion, our study suggested for the first time complex immunoregulatory
effects of PoPEx on T cells, which could assist in the suppression of chronic inflammatory and
autoimmune diseases.