T-Cell Specific Deletion of PTPN23 Alters T-Cell Development and TCRαβ/γδ Composition

Abstract

Highlights What are the main findings? T-cell–specific deletion of PTPN23 causes a marked reduction in T-cells, accompanied by preferential accumulation of TCRγδ T-cells and enrichment of differentiated effector/memory T-cell subsets. Multi-omics and single-cell RNA sequencing reveal alterations in T-cell developmental states, maturation-associated programs, and immune homeostasis following PTPN23 deletion. What are the implications of the main findings? These findings identify a novel function of PTPN23 associated with T-cell development, differentiation, and immune homeostasis. This study provides a basis for future studies investigating whether PTPN23 contributes to dysregulated T-cell responses, including inflammatory disorders and cancer. Abstract T-cells are major therapeutic targets in cancer and immune-mediated diseases. Their development and differentiation require highly dynamic receptor turnover. Protein tyrosine phosphatase non-receptor type 23 (PTPN23) encodes a ubiquitously expressed pseudophosphatase involved in trafficking and internalization of specific cell receptors. Although PTPN23 has essential functions in several cell types, its role in T-cells remains unknown. We therefore investigated the role of PTPN23 in T-cells. We generated transgenic mice lacking PTPN23 specifically in T-cells (PTPN23-CD4-Cre). Flow cytometry, single-cell RNA sequencing (scRNA-seq), and proteomic analysis were performed in lymphoid and mucosal organs. PTPN23-CD4-Cre mice exhibited a significant reduction in total T-cell numbers in lymphoid organs, accompanied by increased proportions and numbers of γδ T-cells and markedly reduced naïve T-cells. Similar findings were made in mucosal organs, with γδ T-cell levels rising as age increased. In vitro functional assays revealed that residual PTPN23-CD4-Cre T-cells display an altered cytokine profile enriched for inflammatory mediators, a finding that was accompanied by proteomic and phosphoproteomic alterations consistent with changes in T-cell differentiation and inflammatory programs. scRNA-seq analysis showed altered representation of thymocytes along a shared developmental trajectory, with enrichment of PTPN23-deficient T-cells at earlier developmental states. Our study identifies PTPN23 as a previously unrecognized player of T-cell development, differentiation, and immune homeostasis.