DC-intrinsic SHP1 restrains central memory CD8⁺ T cell formation via the TCF-1/Wnt/β-Catenin axis.

The tumor microenvironment (TME) limits durable antitumor immunity by impairing CD8+ T cell responses. Memory like CD8+ T cells are important for long-term immune control but are often restricted in the TME. Dendritic cells (DCs) are key regulators of T cell fate. Previous studies have shown that SHP1 in DCs fosters an immunosuppressive microenvironment and facilitates tumor immune escape. T cell factor-1 (TCF-1), encoded by Tcf7 gene, is required for central memory CD8+ T cell (TCM) formation and is closely linked to canonical Wnt/β-catenin signaling. However, whether SHP1 in DCs regulates TCF-1 expression and TCM formation remains unclear. To investigate the role of DC intrinsic SHP1 in T cell immunity, SHP1 deficient DC2.4 cells and primary bone marrow derived dendritic cells (BMDCs) were co-cultured with OT-1 T cells to assess proliferation, TCM formation, cytotoxic activity, and TCF-1 expression. A DC-specific SHP1 knockout mice model was used to evaluate antitumor immunity in vivo, and Tcf7 or Ctnnb1 silencing was used to probe the TCF-1/Wnt/β-catenin axis. SHP1 downregulation in DCs markedly enhanced CD8+ T cell proliferation, promoted the generation of CD62L+ CD44+ central memory T cells, and potentiated B16-F10-OVA tumor cell killing, accompanied by increased TCF-1 expression in OT-1 T cells. In DC-specific SHP1 knockout mice, EO771 tumor growth was suppressed with concurrent increases in intratumoral IFN-γ+ and TCF-1+ CD8+ T cell frequencies. Mechanistically, we found that DC SHP1 regulates TCM formation via TCF-1, as silencing Tcf7 in OT-1 T cells abrogated this effect. SHP1-deficient DCs activated Wnt/β-catenin signaling in CD8+ T cells, as shown by increased active β-catenin, total β-catenin, c-Myc and Cyclin D1, and a reduced phospho β-catenin/total β-catenin ratio. Critically, Ctnnb1 silencing in T cells abrogated the enhanced proliferation, TCM formation, and cytotoxic activity induced by SHP1-deficient DCs. DC-intrinsic SHP1 restrains central memory CD8+ T cell formation via the TCF-1/Wnt/β-catenin axis.