Kidney Week

Abstract: SA-OR071

Targeting Senescence-Associated T Cells Reduces Tertiary Lymphoid Structures and Ameliorates Kidney Injury

Session Information

• Maladaptive Kidney Repair and Fibrosis: Novel Therapeutic Targets
  October 24, 2026 | Location: Mile High Ballroom 1D, Convention Center
  Abstract Time: 05:40 PM - 05:50 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Yoshikawa, Takahisa, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto Prefecture, Japan

Takahisa Yoshikawa, MD, PhD

• Taniguchi, Keisuke, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto Prefecture, Japan

Keisuke Taniguchi, MD

• Sato, Yuki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto Prefecture, Japan

Yuki Sato, MD, PhD

• Kohno, Kenji, Graduate School of Science, University of Hyogo, Harima Science Garden City, Japan

Kenji Kohno, PhD

• Takahashi, Satoru, Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki, Japan

Satoru Takahashi, MD, PhD

• Nagata, Satoshi, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki City, Osaka, Japan

Satoshi Nagata, PhD

• Kamada, Haruhiko, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki City, Osaka, Japan

Haruhiko Kamada, PhD

• Sumiyoshi, Takayuki, Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Takayuki Sumiyoshi, MD, PhD

• Kobayashi, Takashi, Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Takashi Kobayashi, MD, PhD

• Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto Prefecture, Japan

Motoko Yanagita, MD, PhD

Background

Tertiary lymphoid structures (TLSs) develop in aged injured kidneys with maladaptive repair. CD153⁺PD-1⁺CD4⁺ senescence-associated T (SA-T) cells promote TLS expansion by interacting with age-associated B cells via CD153-CD30 signaling. However, it remains unclear whether treatments targeting SA-T cells reduce TLS size and ameliorate kidney injury.

Methods

We generated CD153 knock-in (CD153KI) mice, expressing enhanced green fluorescent protein (EGFP) and human diphtheria toxin receptor (hDTR) downstream of the CD153 promoter to trace and deplete CD153⁺ cells. Ischemia-reperfusion injury (IRI) was performed on aged CD153KI mice to induce renal TLSs, followed by diphtheria toxin (DT) administration. Furthermore, anti-CD153 antibodies were also tested in aged wild type after IRI. TLS size and kidney injury were analyzed using histology, flow cytometry, and gene expression analyses. Co-culture of CD4⁺ T cells and fibroblasts was also performed. In addition, single-cell RNA-sequencing (scRNA-seq) of immune cells in human kidneys with TLSs were performed and validated histologically.

Results

SA-T cells expressed EGFP and hDTR within TLSs, whereas naïve CD4⁺ T, CD8⁺ T, CD11b⁺ myeloid, CD19⁺ B, and parenchymal cells did not express EGFP. DT administration reduced SA-T cells, accompanied by rapid TLS regression. The expressions of Il21 and Ifng, the cytokines expressed by SA-T cells and contributing to B cell differentiation, were also decreased. EdU cell proliferation assay demonstrated decreased proliferation of T and B cells within TLSs. Moreover, the expression of Cxcl9, Ccl19, and Tnfsf13b in fibroblasts within TLSs diminished, and co-culture of CD4⁺ T cells and fibroblasts promoted Cxcl9 and Ccl19 expression in fibroblasts. In wild type mice, anti-CD153 antibody treatment reduced TLS size and ameliorated kidney injury. In the human kidney with TLSs, scRNA-seq of immune cells identified the TNFSF8 (encoding CD153)^highCD4⁺ T cells, including follicular helper T-like cells. Histological analyses confirmed TNFSF8⁺ T cells within TLSs.

Conclusion

Our study demonstrated that SA-T cells are essential for TLS formation through interacting with B cells and fibroblasts. Targeting SA-T cells led to TLS regression and improvement of kidney injury. Importantly, analogues of TNFSF8⁺CD4⁺ T cell population were identified in human renal TLSs, supporting the translational relevance of our findings.

Acknowledgment

We thank the Single-Cell Genome Information Analysis Core (SignAC) at WPI-ASHBi, Kyoto University for their support. We also thank the support by the World Premier International Research Center Initiative (WPI), MEXT, Japan. We would like to express our sincere gratitude to Professor Hiroshi Kawamoto for providing us with the opportunity to use the flow cytometry facility, and to Professor Seiji Ogawa for allowing us to use the single-cell RNA-seq device.

Funding

• Private Foundation Support