Mitochondria and Lysosomes Team Up to Control Immune Tolerance Cells

Regulatory T (Treg) cells are critical gatekeepers of immune tolerance—their depletion or dysfunction leads to autoimmunity, while their excess in tumors suppresses anti-cancer immunity. Understanding how Treg cells functionally adapt during inflammation or therapeutic targeting is therefore a central challenge in immunology.

Using a mouse model of acute inflammation driven by Treg cell depletion via diphtheria toxin, researchers at St. Jude identified four distinct Treg cell states distinguished by surface expression of PD-1 and CXCR3. Single-cell RNA sequencing, pseudotime analysis, and adoptive transfer experiments showed these states form a differentiation hierarchy: from a quiescent PD-1−CXCR3− state through intermediate activated states to a terminally differentiated, quiescence-resetting PD-1−CXCR3+ state. Metabolic profiling confirmed that activated intermediate states had the highest mitochondrial oxidative phosphorylation and glycolysis, while terminal cells reverted to metabolic quiescence.

To probe the role of mitochondrial dynamics, the team deleted Opa1—a protein governing mitochondrial inner membrane fusion—specifically in Treg cells. Opa1-deficient mice developed pronounced systemic inflammation, with reduced generation of high-metabolic, highly suppressive Treg cells. Mechanistically, Opa1 loss triggered mitochondrial bioenergetic stress, elevated AMPK signaling, and nuclear translocation of the lysosomal transcription factor TFEB, linking mitochondrial dysfunction to lysosomal signaling.

A parallel Treg cell-specific deletion of Flcn—a lysosomal protein that normally restrains TFEB—partially reproduced the inflammation seen with Opa1 loss. Critically, simultaneous deletion of TFEB rescued this phenotype, confirming that aberrant TFEB activation is a key downstream driver. Flcn-deficient Treg cells were enriched in the terminal metabolic quiescence reset state, failed to accumulate in non-lymphoid tissues such as the colon and visceral adipose tissue, and were unable to suppress anti-tumor immunity in vivo.

These findings establish that mitochondria and lysosomes cooperate through an Opa1–AMPK–TFEB axis to balance Treg cell metabolic heterogeneity and functional states. The identification of organelle-directed signaling as a regulator of Treg cell fitness opens potential new avenues for therapeutic modulation—either enhancing Treg function in autoimmunity or impairing it in cancer.