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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 5

TNF superfamily members CD153 and CD30 are specifically expressed in SAT cells and ABCs, respectively, inside of TLTs in aged injured kidneys.

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TNF superfamily members CD153 and CD30 are specifically expressed in SAT...
(A) Dot plot of ligand-receptor interactions related to TNF superfamily members between 6 CD4+ T cell subpopulations and 3 B cell subpopulations identified by scRNA-Seq (see Figure 3). (B) Violin plots showing the expression of Tnfsf8 and Tnfrsf8 in all CD45+ cells. The putative identities of each cluster are specified in the box. DN, double-negative. (C) UMAP plot of Tnfsf8 and Tnfrsf8 in CD45+ cells in Figure 2B and enlargement of those of Cd4, Tnfsf8, Spp1, Sostdc1, Il21, and Il10, and those of Cd19, Cr2, Tbx21, and Tnfrsf8. (D) Representative FACS plots of CD153 expression on T cells, B cells, macrophages, dendritic cells, CD4+ T cells, CD8+ T cells, CD44hiCD4+ T cells, and PD-1+CD4+ T cells (n = 3/group). (E) Representative FACS plots of CD30 expression on T cells, B cells, macrophages, and dendritic cells (n = 2/group). (F) Plasma soluble CD30 (sCD30) levels of young and aged mice with or without (not treated, NT) ischemic reperfusion injury (IRI) induction (n = 3/group, samples were collected 45 days after IRI). Data are presented as mean ± SD. Statistical significance was determined by 1-way ANOVA with Bonferroni’s post hoc analysis. ***P < 0.001. (G) Violin plots showing the expression of Adam10 and Adam17 among 3 B cell subsets identified by scRNA-Seq. (H) Representative ISH images of Tnfsf8 and Tnfrsf8 in aged kidneys 45 days after IRI, and (I) ISH with immunofluorescent costaining for p75NTR, a TLT-associated fibroblast marker, of the aged kidneys. The red dashed lines in H and white arrows in I indicate the localization of TLTs. A magnified view of the outlined box is shown in the middle in H and in the right in I. Scale bars: 50 μm.

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

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