Loss of DUSP2–RPA signaling enhances virtual memory T cell–mediated innate-like antiviral immunity
Year: 2026
Type: article
Abstract: Virtual memory CD8 + T (T VM ) cells are antigen-inexperienced cells with rapid effector potential, but how their differentiation and antiviral activity are regulated remains unclear. Here, using an autoantibody-based screening strategy, we identify the phosphatase DUSP2 as a key regulator of T VM cell responses. Dual-specificity phosphatase 2 (DUSP2) deficiency enhances CD8 + T cell–dependent antiviral immunity and promotes the expansion of a highly activated CD44 super-high T VM subset. Upon viral challenge, these T VM cells respond rapidly without antigen recognition and display enhanced effector and cytokine programs, supporting an innate-like mode of antiviral immunity rather than conventional antigen-specific recall. Mechanistically, DUSP2 interacts with the replication protein A (RPA) complex to regulate RPA2 phosphorylation and chromatin association. Disruption of the DUSP2–RPA axis promotes R-loop accumulation and increases chromatin accessibility, which in turn activates Eomesodermin (EOMES)-associated transcriptional programs, eventually promoting T VM cell differentiation. T cell–specific deletion of RPA1 phenocopies these effects, leading to spontaneous T VM cell accumulation and rapid effector-like responses upon viral challenge. Together, our findings establish a DUSP2–RPA–R-loop axis that restrains T VM cell development and innate-like antiviral immunity.
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7225652461