Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model

Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model

UL16-binding protein 2 (ULBP2), a ligand for the activating receptor NKG2D, plays a dual role in tumor immunity, promoting immune activation or suppression, depending on the context. To investigate its impact on CD4<sup>+</sup>CD25<sup>+</sup> T cell-targeted immunotherapies,...

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Bibliographic Details
Main Authors: Yasuhiko Teruya, Kosuke Yamaguchi, Kohei Yamane, Naomi Miyake, Yuji Nakayama, Takafumi Nonaka, Hiroki Chikumi, Akira Yamasaki
Format: Article
Language:English
Published: MDPI AG 2025-06-01
Series:Cells
Subjects:
ULBP2
NKG2D ligands
NKG2D
tumor immunology
CD4<sup>+</sup> T cells
Treg
Online Access:https://www.mdpi.com/2073-4409/14/12/893
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Summary:UL16-binding protein 2 (ULBP2), a ligand for the activating receptor NKG2D, plays a dual role in tumor immunity, promoting immune activation or suppression, depending on the context. To investigate its impact on CD4<sup>+</sup>CD25<sup>+</sup> T cell-targeted immunotherapies, we used a syngeneic CT26 colon cancer model engineered to express ULBP2 and compared tumor growth and tumor-infiltrating lymphocyte (TIL) profiles in control and ULBP2-expressing tumors treated with anti-CD4, anti-CD25, or anti-CTLA-4 antibodies. Tumor growth was uniformly assessed on day 21 post-transplantation, and TIL analysis was performed in groups with evaluable residual tumors. Anti-CD4 antibody significantly suppressed tumor growth in mock-transfected tumors, while no significant suppression was observed in ULBP2-expressing tumors. Anti-CD25 antibody had limited efficacy in mock tumors and tended to promote tumor growth in ULBP2-expressing tumors. Following these treatments, ULBP2 expression was associated with reduced NKG2D expression in CD8<sup>+</sup> effector memory T cells, particularly PD-1<sup>high</sup> subsets. In contrast, anti-CTLA-4 antibody treatment induced marked tumor regression irrespective of ULBP2 expression. These findings suggest that ULBP2–NKG2D signaling may contribute to altered CD8<sup>+</sup> T cell phenotypes under T cell-modulatory conditions, potentially impacting the outcome of CD4<sup>+</sup>CD25<sup>+</sup> T cell-targeted therapies and providing insights for optimizing immunotherapeutic strategies.
ISSN:2073-4409

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