Kidney Resident Memory CD8+ T cells drive the immortality of hypertension

Hypertension remains the leading cause of cardiovascular disease, impacting most American adults. Although clinical management can transiently control blood pressure, hypertension often rebounds with a lapse in treatment, implying the presence of a long-lived memory that could be targeted for the eradication of hypertension. Towards this end, decades of research have demonstrated a renal driver of memory through kidney transplantation studies, yet the identity of the perpetrators remained unknown. We have observed a persistent CD8+ T cell population within the kidneys of hypertensive patients and hypothesize that resident memory CD8+ T cells (CD8Trms) form and anchor hypertension within the kidney and drive the chronic progression and recurrence of hypertension. Investigation began by identifying CD8Trm in the kidneys of hypertensive patients and multiple mouse models, including the classic DOCA-salt model and two novel models of high-salt induced recurrence of hypertension after an initial period of stimulation with aldosterone or angiotensin II. CD8Trm abundance and sodium transporter expressions were assessed using multiplex immunofluorescence and high-dimensional flow cytometry. Mouse models were applied in wild-type (WT), Rag2OT-I, or T cell-specific TGFβRII KO (TSP-TGFβR-KO) mice, the latter of which are unable to establish Trms. Blood pressure was monitored via biotelemetry. Moreover, ex vivo studies using WT and TSP-TGFβR-KO CD8Ts further define the hypertensive stimuli that drive CD8Trm formation, which was characterized by flow cytometry, cytokine production, and single-cell metabolic profiling. Finally, the co-culture of these ex vivo CD8Trms with mouse DCT cells examined the impact of CD8Trms on distal nephron sodium retention. The kidneys from hypertensive patients contained a significant CD8Trm population, a finding consistently observed across all mouse models examined. These CD8Trm (CD45.2i.v.-CD3+CD8+CD69+CD103+) remained at high numbers in the kidney after blood pressure normalization, contributing to a later high-salt-induced hypertension recurrence. Additionally, NCC expression was sustained at high levels, correlating with increased CD8Trm number. To determine if CD8Trm require an antigen for development, DOCA-salt was given to Rag2OT1 mice without OVA peptide activation, and a significant CD8Trm population developed, suggesting antigen-independent development. Rather, the CD8Trm formed during hypertension exhibited significant expression of the ATP-sensor P2X7. Ex vivo treatment of CD8Ts revealed that ATP-driven CD8T activation in combination with the known memory-inducer, TGFβ, led to a CD8Trm phenotype with higher CD69+CD103+ expression, cytokine production, and metabolic profile characteristic of a Trm population. Co-culture of these CD8Trms with mDCTs induced NCC-driven sodium retention compared to controls. Importantly, mice lacking Trm formation (TSP-TGFβR-KO) exhibit significantly attenuated hypertension during the DOCA-salt model. Moreover, despite becoming hypertensive during Ang II infusion, they remained protected from high-salt-induced recurrence of hypertension. In summary, our study identified a novel, long-lasting CD8Trm population within the kidney during hypertension. These cells can form through ATP and TGFβ stimulation alone and induce greater sodium retention via stimulating mDCTs. Finally, when this population is absent, the progression of hypertension is limited and recurrence eradicated, suggesting the vital role CD8Trm play in the chronicity and recurrence of hypertension. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.