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CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Yuki Sato, … , Nagahiro Minato, Motoko Yanagita
Yuki Sato, … , Nagahiro Minato, Motoko Yanagita
Published November 23, 2021
Citation Information: J Clin Invest. 2022;132(2):e146071. https://doi.org/10.1172/JCI146071.
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Research Article Inflammation Nephrology Article has an altmetric score of 43

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

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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 6

CD153 is essential for functional SAT cell induction and TLT formation.

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CD153 is essential for functional SAT cell induction and TLT formation.
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Analysis of aged CD153-deficient (CD153–/–) mouse kidneys subjected to ischemic reperfusion injury (IRI). (A) Periodic acid–Schiff staining and (B) Cd4, Cd19, Ifng, Cxcl13, Ccl19, and Il21 mRNA levels (n = 4/group) in WT and CD153–/– mice 45 days after IRI. (C) Cumulative TLT sizes per cortex, and the number of (D) total and (E) advanced-stage TLTs following IRI induction (n = 4/group). (F) OPN production by CD4+ T cells from aged kidneys of WT and CD153–/– mice 45 days after IRI (n = 4/group). Cells were stimulated in bulk culture with PMA and ionomycin. (G) Representative FACS plots and frequencies of ABCs and germinal center B (GCB) cells in WT and CD153–/– mice (n = 3–4/group). (H) Scatter plot comparing normalized RNA-Seq read counts of ABCs from WT and CD153–/– mouse kidneys 45 days after IRI (n = 3/group). Colored dots indicate transcripts with FDR < 0.01. Red and blue dots indicate genes that are significantly upregulated and downregulated, respectively. (I) Experimental protocol of bone marrow transplantation experiments. Bone marrow cells from aged WT and CD153–/– mice were transplanted into lethally irradiated, aged Rag2-deficient (Rag2–/–) mice. After a 6-week recovery period, mice were subjected to IRI and sacrificed on day 45. (J) Immunofluorescence of CD3ε and B220; and CD21, Ki67, and DAPI. (K) Cumulative TLT sizes per cortex and the number of total and advanced-stage TLTs per section (n = 3/group). The arrowheads in A and arrows in J indicate the localization of TLTs. Scale bars: 300 μm (A) and 50 μm (J). 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.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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