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.

Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression

“…TLS are organized aggregates of immune cells that form postnatally in nonlymphoid tissues, usually as a persistent antigen production(50) and generate autoreactive effector cells. TLS have been earlier described in mouse kidney tissue samples (51)(52)(53)(54). Future studies will be needed ( One of the most devastating complications of CKD is its progression to ESRD, which requires life-sustaining dialysis or transplantation (55).…”

“…TLS are organized aggregates of immune cells that form postnatally in nonlymphoid tissues, usually as a persistent antigen production( 50 ) and generate autoreactive effector cells. TLS have been earlier described in mouse kidney tissue samples( 51–54 ). Future studies will be needed to define TLSs in CKD and kidney fibrosis; however, they could have tremendous therapeutic potential.…”

T-Cell Aging-Associated Phenotypes in Autoimmune Disease

“…Age-related autoimmune diseases, such as RA and GCA, occur because autoreactive T cells are recruited to and retained in the tissue niche ( Weyand et al, 2018a ; Weyand and Goronzy, 2021 ). In the case of RA, invading immune cells form tertiary lymphoid structures ( Takemura et al, 2001a ; Takemura et al, 2001b ), an architectural feature that has been also associated with kidney aging ( Sato et al, 2016 ; Sato et al, 2020 ; Sato et al, 2022 ). One hallmark of T cells isolated from RA patients is their ease of being transformed into a mobile T cell that rapidly slips into the synovial tissue to establish sophisticated extra-lymphoid structures, stimulating local stromal cells and functions as the key organizer of tissue inflammation.…”

Immunosenescence: A Critical Factor Associated With Organ Injury After Sepsis

“…Age-dependent tertiary lymphoid tissue formation can promote intra-renal inflammation ( 172 ). Researchers confirmed that CD153 and CD30 signaling may interact with CD153 + PD-1 + CD4 + senescence-associated T cells (SAT) and CD30 + T-bet + age-related B cells, resulting in tertiary lymphoid tissue generation in chronically inflammatory organs, thereby promoting renal inflammation and fibrosis ( 173 ). In addition to ESRD, CD8 + T cell depletion occurs as early as CKD3 in diabetes mellitus, showing the characteristics of aggravated immunosenescence ( 174 ).…”