Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells, 2025, Saravia et al

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Editor’s summary​

Lymphocytes, including regulatory T (Treg) cells, tune their metabolism to support their immunological functions. However, the molecular events controlling Treg cell metabolic reprogramming during inflammation are not fully understood. Using a mouse model of acute inflammation, Saravia et al. found that Treg cells undergo dynamic mitochondrial metabolic and lysosomal reprogramming across heterogeneous activation states. Loss of the proteins Opa1 or Flcn in Treg cells triggered severe inflammation associated with mitochondrial bioenergetic stress and aberrant activation of transcription factor EB (TFEB) that led to excessive lysosomal biogenesis in Treg cells. These findings identify a pathway of interorganelle communication between mitochondria and lysosomes that supports Treg cell–suppressive functions during inflammation. —Claire Olingy

Abstract​

Immunotherapies targeting regulatory T (Treg) cells often trigger inflammation and autoimmunity. How Treg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates Treg cell metabolic and functional fitness. Treg cell–specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of Treg cells with high mitochondrial metabolic and suppressive function.

Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate–activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, Treg cell–specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency–associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient Treg cells were enriched in a terminal “metabolic quiescence reset” state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria–lysosome interplay control Treg cell differentiation and function.

Paywall: https://www.science.org/doi/10.1126/sciimmunol.ads9456

 

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Paper requested by @V.R.T.