ICOSL, TL1A, and GITRL Sustain Memory Th17/Th1-mediated Tissue Inflammation

ABSTRACT: We recently demonstrated that several T cell costimulatory molecules collectively control the long-term maintenance of Th2-driven inflammation. The costimulatory combinations sustaining Th17/Th1-driven inflammation remain poorly defined. scRNA-seq analysis of human and mouse lung Th17/Th1 cells revealed prominent expression of TNFRSF25 (DR3; TL1A receptor), TNFRSF18 (GITR), ICOS, TNFRSF4 (OX40), and TNFSF8 (CD30L). Therapeutic blocking of ICOSL, OX40L, and CD30L in mice with severe Th17/Th1-biased lung inflammation partly reduced tissue activity, whereas blockade of ICOSL, TL1A, and GITRL suppressed maintenance of lung T cell and tissue responses by ~90%. Elevated mRNA expression of Icos, Tnfrsf18, Tnfrsf25, and Tnfrsf4 were also found in Th17/Th1 cells in the CNS of mice with EAE. Therapeutic co-blocking of ICOSL, GITRL, and TL1A delayed relapsing EAE, and additional co-blockade of OX40L limited paralysis relapse as well as CNS inflammation. We identify TL1A and GITRL, in addition to ICOSL and OX40L, as potential molecules to be targeted in combination therapeutic approaches to limit Th17/Th1-driven tissue inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE351804 | GEO | 2026/10/22

REPOSITORIES: GEO