Control of tertiary lymphoid tissue revealed

Abstract

Control of tertiary lymphoid tissue revealed Control of tertiary lymphoid tissue revealed CITATIONS Sato Y, Oguchi A, Fukushima Y, et al. CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury. J Clin Invest. 2022;132(2):e146071. Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues that develop at sites of chronic inflammation and aging. Similar to lymph nodes, TLTs can initiate immune responses and coordinate local tissue immunity. Structurally, TLTs are composed primarily of follicular dendritic cells, T cells, plasmablasts and B cell subsets at various developmental stages. TLTs have been identified in numerous chronic human diseases, including chronic kidney allograft rejection, and their presence has been associated with progressive graft dysfunction, possibly through the promotion of tubular inflammation and interstitial fibrosis. Therefore, understanding the cellular and molecular mechanisms responsible for TLT formation may have major therapeutic implications. In a recent report in the Journal of Clinical Investigation, Sato and colleagues used the unilateral ischemia-reperfusion injury (IRI) model in aged mice to study the mechanism and pathophysiology of TLT development. In a series of elegant experiments, the authors showed that signaling through the tumor necrosis factor (TNF) superfamily members CD153/CD30 between two unique age-dependent lymphocyte populations, i.e., PD-1+CD4+ senescence-associated T (SAT) cells and CD95+CD11b+T-bet+ age-associated B cells (ABCs), is essential for TLT formation. They provided further evidence that activation of the CD153/CD30 pathway also plays a critical role for TLT development in humans as well. The report starts by showing that SAT cells and ABCs are closely associated with TLT formation and that their numbers increase substantially over time during TLT expansion. Bulk and single-cell RNA sequencing (scRNA-seq) of TLTs revealed that, despite expression of the exhaustion marker PD-1, SAT cells are not fully exhausted and produce ABC-inducing factors such as interleukin (IL)-21, IL-10 and interferon (IFN)-γ. To further determine the molecular mechanisms, the authors performed unbiased ligand–receptor interaction studies between CD4+ T cell and B cell populations. These experiments demonstrated that the CD153/CD30 pathway mediates specific interactions between SAT cells and ABCs. Because TNF superfamily molecules are known to be crucial for lymphoid tissue development, this pathway may play a key role in SAT cell–ABC interaction during TLT formation. The authors tested this hypothesis using mice deficient in CD153 or CD30 and showed that both CD153 and CD30 are indispensable for SAT cell induction and age-dependent TLT formation. In addition, these molecules are critical for ABC induction and germinal center B cell preservation in the TLTs, but not for maintenance of the ABC phenotype. Mice with unilateral IRI do not exhibit renal dysfunction because the contralateral healthy kidney compensates for the injured kidney. Therefore, to evaluate the impact of TLT formation on renal function, the authors used the adenine-induced nephropathy model in which mice develop prominent kidney TLTs, progressive kidney fibrosis and renal failure. In this model, genetic deletion of CD153 attenuated TLT formation, reduced fibrosis and improved kidney function, providing a causal link among CD153/CD30 signaling, TLT formation and poor kidney outcomes. To better understand the interactions between SAT cells and ABCs, the authors deciphered the origins of these cell subsets. Through velocity analyses of the scRNA-seq data in combination with T and B cell receptor sequencing analyses of SAT cells and ABCs from both kidney and spleen, they concluded that SAT cells and ABCs in the kidney TLTs are derived locally from tissue-resident CD4+ T cells as well as remotely by recruitment from the spleen. Overall, these data identify a critical role for CD153/CD30 signaling in TLT formation in aged and damaged kidneys, underscoring a previously unappreciated pathway in kidney injury. What is the clinical relevance of these findings to human transplantation? Sato and colleagues showed that, in the synovium of aged individuals with rheumatoid arthritis, peripheral T helper/T follicular cells and ABCs also expressed CD153 and CD30, respectively. Importantly, the authors confirmed the presence of CD153-positive cells within TLTs in human kidneys, especially within germinal centers. This finding strongly supports the idea that mechanisms similar to the ones outlined here in mice are also applicable to humans. Given that SAT cells and ABCs are induced under conditions that accelerate immune aging, such as autoimmune diseases and obesity, the results of this study might apply to other pathological conditions including kidney transplantation. A better understanding of TLT formation and how it affects kidney disease progression may help identify new predictors of renal graft outcomes. More importantly, these findings provide the rationale for future studies to test the hypothesis that therapeutics targeting the CD153/CD30 pathway may prevent progression of kidney injury and loss of kidney allografts.