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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2025-06-01
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| author | Yasuhiko Teruya Kosuke Yamaguchi Kohei Yamane Naomi Miyake Yuji Nakayama Takafumi Nonaka Hiroki Chikumi Akira Yamasaki |
| author_facet | Yasuhiko Teruya Kosuke Yamaguchi Kohei Yamane Naomi Miyake Yuji Nakayama Takafumi Nonaka Hiroki Chikumi Akira Yamasaki |
| author_sort | Yasuhiko Teruya |
| collection | DOAJ |
| description | 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. |
| format | Article |
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| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Cells |
| spelling | doaj-art-ac48921e60844041b51dc4387a4bebea2025-06-25T13:36:36ZengMDPI AGCells2073-44092025-06-01141289310.3390/cells14120893Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor ModelYasuhiko Teruya0Kosuke Yamaguchi1Kohei Yamane2Naomi Miyake3Yuji Nakayama4Takafumi Nonaka5Hiroki Chikumi6Akira Yamasaki7Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, JapanDivision of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, JapanDivision of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, JapanDivision of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, JapanDivision of Radioisotope Science, Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, 86 Nishi-cho, Yonago 683-8503, JapanDivision of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, JapanDivision of Infectious Diseases, School of Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, JapanDivision of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, JapanUL16-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.https://www.mdpi.com/2073-4409/14/12/893ULBP2NKG2D ligandsNKG2Dtumor immunologyCD4<sup>+</sup> T cellsTreg |
| spellingShingle | Yasuhiko Teruya Kosuke Yamaguchi Kohei Yamane Naomi Miyake Yuji Nakayama Takafumi Nonaka Hiroki Chikumi Akira Yamasaki Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model Cells ULBP2 NKG2D ligands NKG2D tumor immunology CD4<sup>+</sup> T cells Treg |
| title | Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model |
| title_full | Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model |
| title_fullStr | Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model |
| title_full_unstemmed | Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model |
| title_short | Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8<sup>+</sup> T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model |
| title_sort | ectopic ulbp2 is associated with decreased nkg2d expression in cd8 sup sup t cells under t cell modulatory conditions in a murine tumor model |
| topic | ULBP2 NKG2D ligands NKG2D tumor immunology CD4<sup>+</sup> T cells Treg |
| url | https://www.mdpi.com/2073-4409/14/12/893 |
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