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.
Highlights
Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues that facilitate local T and B cell interactions in chronically inflamed organs [1,2,3]
Despite some expression of mRNA (Figure 1G), senescence-associated T (SAT) cells in the kidneys lacked cell-surface expression of CXCR5 (Figure 1H), which is a marker of follicular helper T cells (Tfh), a subset of CD4+ T cells that are specialized in providing help to B cells within germinal center (GC) in lymph nodes and spleen [30]
We show that CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, SAT cells and associated B cells (ABCs), is required to promote age-dependent TLT expansion (Figure 12)
Summary
Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues that facilitate local T and B cell interactions in chronically inflamed organs [1,2,3]. TLTs initiate antigen-driven immune responses and underlie chronic inflammation. TLTs have been identified in various human diseases, including cancer, infection, and autoimmunity [1,2,3]. Aging has recently been identified as a predisposing factor for TLT development [4,5,6]. Acute kidney injury (AKI) is a global public health problem resulting in 1.7 million deaths annually [7]. The prognosis of AKI in the elderly is poor and often progresses to chronic kid-
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