Abstract
BACKGROUND: Recent single-cell studies indicated that IL-17-producing T cells (T17) have diverse subsets expressing IL-17A, IL-17F, or a combination in human psoriasis skin. However, it is unknown how T17 subsets are differently regulated by IL-23 versus IL-17A blockade. OBJECTIVE: We sought to investigate how systemic monoclonal antibody injections blocking IL-23 versus IL-17A differently modify immune cell transcriptomes in human psoriasis skin. METHODS: We analyzed a total of 93 human skin single-cell libraries, including 42 psoriasis pretreatment lesional skin, 25 psoriasis pretreatment nonlesional skin, 12 psoriasis posttreatment after IL-23 inhibition, 4 psoriasis posttreatment after IL-17A inhibition, and 10 control skin samples. CLINICALTRIALS: gov NCT04630652. RESULTS: Of the six T17 subsets identified, an IL17A(+)IFNG(+) subset and an IL17F(+)IL10(-) subset expressed the IL-23 receptor along with other inflammatory cytokines, and IL-23 inhibition downregulated these potentially 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 nonpathogenic T17 subset increased after IL-23 inhibition. In addition, 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. CONCLUSIONS: This study suggests multiple immune mechanisms of how IL-23 inhibition can modify the complex inflammatory environment present in psoriatic skin, highlighting the roles of specific T17 subsets in psoriasis development and background skin protection.