Peripheral γδ T-cell remodeling in psoriasis is associated with effector-biased transcriptional organization and reduced representation of a circulating CSMD1-marked state

Abstract

Background Despite the prominent immune dysregulation in psoriasis, the organization of peripheral blood γδ T cell states remains incompletely defined. Methods Here, we performed single-cell transcriptomic profiling of enriched peripheral blood-derived γδ T cells from healthy donors and patients with psoriasis. By integrating state annotation, inferred transcriptional ordering, ligand–receptor communication, transcriptome–inferred metabolite–sensor communication, and regulatory network analyses, we constructed a circulating γδ T-cell state atlas. Results We identified eight γδ T-cell states. Within the resolution of this dataset, psoriasis-derived cells did not form a clearly separated disease-exclusive state; instead, disease-associated changes were mainly reflected by altered representation and transcriptional organization of pre-existing states, including reduced peripheral representation of a CSMD1-marked γδ T-cell state. Pseudotime analysis arranged γδ T cells along an inferred activation- and cytotoxicity-associated transcriptional continuum, with Naive-like cells at the lower-pseudotime region and cytotoxic effector-, NK-like-, cytotoxic memory-like-, terminal-branch-, and CSMD1-marked states toward higher-pseudotime regions. Psoriasis-derived γδ T cells were more frequent in cytotoxicity-related regions. This pattern suggests a shift toward effector states. In parallel, peripheral γδ T cell communication suggested cytotoxic-state-biased ligand–receptor patterns, with rewiring of MIF-related and metabolic signaling and reduced network participation of CSMD1+ γδ T cells. Regulatory analyses further linked FOXP1, STAT1, and NFATC3 as candidate regulators associated with early-like, transitional/CSMD1-marked, and cytotoxic-associated transcriptional states, respectively. Conclusions These findings support a state-resolved framework of circulating γδ T-cell remodeling in psoriasis and identify reduction and possible redistribution of a CSMD1-marked late-stage state as a feature of disease-associated immune remodeling.