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

Tertiary lymphoid tissues (TLTs) facilitate local T- and B-cell interactions in chronically inflamed organs. Although TLTs are induced in aged injured kidneys, the cellular and molecular details as well as the impact on kidney function remain unexplored. Here, we identify TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, CD153+PD1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells and ABCs progressively accumulated within TLTs in aged kidneys after injury. By scRNAseq, SAT cells were further divided into two subpopulations, T peripheral helper-like (Tph-like) cells and IL10-producing T cells. In kidney injury models, CD153 or CD30 deficiency reduced ABC numbers, resulting in attenuated TLT formation with improved inflammation, fibrosis and renal function. Mechanistically, SAT cells from CD30-deficient mice exhibited decreased expression of Il21 and Il10, indicating CD153-CD30 signaling was required for SAT cells to acquire B cell helper functions. Clonal analysis showed that SAT cells in the kidneys arose from both local differentiation and recruitment from the spleen. Human Tph cells and ABCs also expressed CD153 and CD30, respectively. These results suggest that targeting CD153-CD30 signaling pathway might be effective for preventing TLT expansion and kidney disease progression.