Regulatory T cells (Tregs) are essential for resolving inflammation and maintaining immune homeostasis. How Tregs are locally regulated in inflamed niches is poorly understood, although their expression of CD4 helper T (Th) cell lineage-defining transcription factors (i.e. Gata3, Rorγt, and Tbet) tailors their regulatory function towards a specific type of inflammation. We discovered that IL-33, a critical driver of type-2 immunity, promotes the local expansion of Gata3high Tregs via an indirect cellular mechanism involving group 2 innate lymphoid cells (ILC2). More specifically, IL-33 stimulates tissue-resident ILC2 to secrete CCL1 and express surface OX40L, which is essential for the recruitment and local expansion of Gata3high Tregs in multiple organs. This showed that tissue-resident ILC2 are a critical regulatory hub for local Treg expansion in type-2 inflammation.
However, ILC2 can also promote type-2 Th (Th2) cells via OX40L-OX40 signaling, and we asked why ILC2 would simultaneously engage Th2 cells and Gata3high Tregs in inflamed tissues. Using OX40ΔTreg mice (where only the ILC2-Treg interaction is impaired) we observed unrestrained Th2 cell-driven inflammation after allergen exposure. This indicated that ILC2- Treg interactions were important for locally controlling Th2 cells. Mechanistically, we discovered that Gata3high Tregs control the bioavailability of OX40L on ILC2 via a negative feedback circuit, which in turn influenced the formation of effector memory Th2 cells. Hence, local Treg-mediated control of adaptive type-2 immunity is contingent on interactions with ILC2 via the OX40L-OX40 signaling axis. These findings also highlight the dualistic nature of OX40 on both effector and regulatory T cell biology, which may stimulate a re-evaluation of this molecule for therapeutic purposes.
Science Immunology
19 Jul 2024
Vol 9, Issue 97
DOI: 10.1126/sciimmunol.adl1903