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

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 12

A model for interaction between SAT cells and ABCs within TLTs in aged injured kidneys.

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A model for interaction between SAT cells and ABCs within TLTs in aged i...
(A) SAT cells in aged injured kidneys are defined as CD153+CD44hiPD1+CXCR5–CD4+ T cells by flow cytometry. SAT cells are classified into Tph-like cells and Th10 at transcriptional levels. (B) SAT cells express PD-1 and CD153 on their surface, whereas ABCs are positive for transcriptional factor T-bet, and express CD11b and CD95 on their surface. SAT cells produce IL-21, IL-10, and IFN-γ, all of which are essential for the induction of ABCs and germinal center B (GCB) cells and the acquisition of these B cell helper functions of SAT cells is dependent on CD153/CD30 signaling. In the absence of CD153/CD30 signaling, SAT cells lose their B cell helper function and are not fully capable of inducing ABCs and GCB cells, resulting in a reduction in number and size of TLTs. Cell-surface CD30 is quickly lost after activation by shedding and becomes the soluble form of CD30 (sCD30).