mTOR drives tertiary lymphoid tissue formation and growth in the kidney

Daniel AtwoodZhibin HeMakoto MiyazakiKatharina HoppSarah FaubelCharles Edelstein^*

• University of Colorado Anschutz Medical Campus, Aurora, United States

Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues that develop de novo in nonlymphoid organs. In this study, we show that the kidneys of aged mice with a renal tubule-specific knockout of autophagy-related 7 (Atg7) have numerous and large tertiary lymphoid tissues (TLTs). p-S6 protein, a marker of mTORC1, was increased in the tubules in close proximity to the TLTs and in the TLTs. In Atg7-/- kidneys there was tubular injury and increased proinflammatory cytokines, that are known to promote TLT growth. In mice with either polycystic kidney disease (Pkd1RC/RC) or kidney ischemia, there was increased p-S6 in tubules in close proximity to TLTs and in TLTs. Treatment with Torin2, an mTOR inhibitor, resulted in the virtual disappearance of TLTs in Pkd1RC/RC kidneys and a significant reduction of TLTs in ischemic kidneys. To determine whether p-S6 in the tubules was driving TLTs, ischemia was induced in tubule-specific Atg7-/- Raptor (mTORC1) -/- mice. Tubule-specific Raptor knockout had little effect on the TLTs. In summary, Torin2 that inhibited p-S6 in both tubules and TLTs resulted in a large decrease in TLTs in ischemic and Pkd1RC/RC kidneys. Tubule-specific knockout of mTORC1 (Raptor) had no effect on TLTs. In conclusion, p-S6 activity within the TLTs and not p-S6 activity in tubules results in proliferation of immune cells in TLTs and TLT formation and growth. These data provide new information on the role of mTOR in the formation and growth of TLTs. The study has important therapeutic implications as TLTs are present in many disease processes and mTOR inhibitors are used in clinical practice.