Systemic IL-23 blockade downregulates IL-23 receptor-expressing Type 17 T-cell subsets and upregulates regulatory gene expression in myeloid cells in human psoriasis skin

Recent single-cell studies indicated that IL-17-producing T-cells (T17) have diverse subsets expressing IL-17A, IL-17F, or a combination of them in human psoriasis skin. However, it is unknown how T17 subsets are differently regulated by IL-23 versus IL-17A blockades. Here, we studied 93 human psoriasis or control skin single-cell libraries from 42 subjects to understand how IL-23 versus IL-17A systemic blockades differently modify single-cell transcriptome of T17 cell subsets, dendritic cells/myeloid cells, and keratinocytes. Our study shows that IL-23 inhibition down-regulates IL-23 receptor-expressing pathogenic T17 subsets. In contrast, T17 cells expressing both IL-17A and IL-17F did not express the IL-23 receptor, and the percentage of this potentially non-pathogenic T17 subset increased after IL-23 inhibition. We also found out that the expression of the IL-17 negative regulation genes, such as TNFAIP3, increased in myeloid cells more after IL-23 inhibition than after IL-17A inhibition. These findings explain why the risk of candidiasis is not increased after IL-23 inhibition, unlike IL-17 inhibition, and the higher efficacy of IL-23 blockades for inducing psoriasis remission in the long term or suppressing relapses after stopping the injections compared to IL-17A blockades.