CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Yuki Sato, Akiko Oguchi, Yuji Fukushima, Kyoko Masuda, Naoya Toriu, Keisuke Taniguchi, Takahisa Yoshikawa, Xiaotong Cui, Makiko Kondo, Takeshi Hosoi, Shota Komidori, Yoko Shimizu, Harumi Fujita, Li Jiang, Yingyi Kong, Takashi Yamanashi, Jun Seita, Takuya Yamamoto, Shinya Toyokuni, Yoko Hamazaki, Masakazu Hattori, Yasunobu Yoshikai, Peter Boor, Jürgen Floege, Hiroshi Kawamoto, Yasuhiro Murakawa, Nagahiro Minato, Motoko Yanagita
Yuki Sato, Akiko Oguchi, Yuji Fukushima, Kyoko Masuda, Naoya Toriu, Keisuke Taniguchi, Takahisa Yoshikawa, Xiaotong Cui, Makiko Kondo, Takeshi Hosoi, Shota Komidori, Yoko Shimizu, Harumi Fujita, Li Jiang, Yingyi Kong, Takashi Yamanashi, Jun Seita, Takuya Yamamoto, Shinya Toyokuni, Yoko Hamazaki, Masakazu Hattori, Yasunobu Yoshikai, Peter Boor, Jürgen Floege, Hiroshi Kawamoto, Yasuhiro Murakawa, Nagahiro Minato, Motoko Yanagita
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Research Article Inflammation Nephrology

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

Abstract

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

Authors

Yuki Sato, Akiko Oguchi, Yuji Fukushima, Kyoko Masuda, Naoya Toriu, Keisuke Taniguchi, Takahisa Yoshikawa, Xiaotong Cui, Makiko Kondo, Takeshi Hosoi, Shota Komidori, Yoko Shimizu, Harumi Fujita, Li Jiang, Yingyi Kong, Takashi Yamanashi, Jun Seita, Takuya Yamamoto, Shinya Toyokuni, Yoko Hamazaki, Masakazu Hattori, Yasunobu Yoshikai, Peter Boor, Jürgen Floege, Hiroshi Kawamoto, Yasuhiro Murakawa, Nagahiro Minato, Motoko Yanagita

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Figure 7

CD30 is also essential for functional SAT cell induction and TLT formation.

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CD30 is also essential for functional SAT cell induction and TLT formati...
Analysis of aged CD30-deficient (CD30–/–) mouse kidneys subjected to IRI. (A) Periodic acid–Schiff (PAS) staining and (B) Cd4, Cd19, Ifng, Cxcl13, Ccl19, and Il21 mRNA levels (n = 4/group) in WT and CD30–/– mice 45 days after ischemic reperfusion injury (IRI). The yellow arrowheads indicate the localization of TLTs. Scale bars: 300 μm. (C) Cumulative TLT size per cortex, and the number of (D) total and (E) advanced-stage TLTs following IRI induction (n = 4/group). (F) Representative FACS plots and frequencies of SAT cells (n = 4), and (G) those of ABCs and germinal center B (GCB) cells in WT and CD30–/– mice (n = 4/group). (H and I) Scatter plots comparing normalized RNA-Seq read counts of (H) SAT cells and (I) ABCs from WT and CD30–/– mouse kidneys 45 days after IRI (n = 3 per group). Colored dots indicate transcripts with FDR < 0.01. Red and blue dots indicate genes that are significantly upregulated and downregulated, respectively. Data are presented as mean ± SD, and statistical significance was determined by an unpaired, 2-tailed t test. *P < 0.05; **P < 0.01; ***P < 0.001. NS, not significant.