Objective: In accordance with previous studies implicating the immune system in the development of hypertension, we found that CD8+ T cells (CD8Ts) infiltrate the kidneys and stimulate distal convoluted tubular cells (DCTs), to upregulate sodium-chloride co-transporter (NCC) activity, leading to excessive salt retention. However, the precise molecules driving this direct interaction between CD8Ts and DCTs have not yet been identified. Here we hypothesize that gamma interferon (IFNg), released by activated CD8Ts, primes the tubular cell to promote interactions between activated CD8Ts and DCTs during the development of salt-sensitive hypertension. We predict blocking this molecular pathway will reduce CD8T-homing into the kidney, lowering blood pressure. Design & Method: In co-culture of mouse CD8Ts and DCTs, recombinant mIFNg, IFNg-neutralizing antibody, and specific siRNAs against the IFNg-receptor or PDL1 were used to determine the role of IFNg-PDL1 pathway in the CD8T-DCT interaction. To validate these studies, we employed IFNg knockout (KO) mice, mice with systemically blocked PDL1 using anti-PDL1 antibody or with renal tubule-specific knockdown of PDL1 (mediated via nanoparticles) in the DOCA-salt model and the CD8T adoptive transfer hypertension models. Blood pressure was monitored using radio-biotelemetry. Endpoint analysis involved flow cytometry, RT-qPCR, and western blot, and immunohistochemistry. Results: We found that CD8Ts isolated from DOCA-salt treated hypertensive mice produce more IFNg and exhibit augmented ability to interact with DCTs compared to those from sham normotensive mice. IFNg stimulation to mDCTs increased expression of CD8-specific antigen presenting molecule MHC-I and CD8T-co-signaling molecule PDL1, which enhanced the interaction between CD8Ts and DCTs, consequently upregulating NCC expression in DCTs, leading to enhanced salt retention. These effects on MHC-I, PDL1, or NCC expression were abolished by neutralizing IFNg in co-culture of DCTs and activated CD8Ts, and knockdown of PDL1 in DCTs blunted NCC expression and sodium retention. In-vivo results verified the in-vitro studies. We found that in both IFNg-KO mice and WT mice receiving PDL1-antagonizing antibodies, DOCA-salt treatment failed to elevate their blood pressure and reduced T cell infiltration and NCC expression within their kidneys compared to WT mice receiving the same treatment (anti-PDL1 results shown in Figure 1). Similar results were observed in DOCA-salt treated mice with renal tubule-specific knockdown of PDL1. Conclusion: In salt-sensitive hypertension, activated CD8Ts demonstrate enhanced ability to interact with DCTs leading to increased expression of NCC and sodium retention through a IFNg-PDL1 pathway mediated mechanism. Blocking the IFNg-PDL1 pathway prevents CD8T-DCT interaction both in vitro and in vivo, ameliorating hypertension.