The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension

Background: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. Methods: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8(+) T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFN gamma)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis. Results: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-gamma-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-gamma or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models. Conclusions: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFN gamma-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.

Automated summary

This study investigated the interaction between CD8T cells and DCTs and its impact on hypertension. The results showed that activated CD8T cells enhance the interaction with DCTs through the upregulation of MHC-I and PDL1 on DCTs via IFN-gamma, leading to increased NCC expression in DCTs, excessive salt retention, and persistent elevation of blood pressure. Eliminating IFN-gamma or specific knockdown of PDL1 on DCTs prevented T cell homing into the kidney, thereby attenuating hypertension.