Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity

Regulatory T cells (T_regs) are essential for resolving inflammation and maintaining immune homeostasis. How T_regs 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 Gata3^high T_regs 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 Gata3^high T_regs 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 Gata3^high T_regs in inflamed tissues. Using OX40ΔT_reg mice (where only the ILC2-T_reg interaction is impaired) we observed unrestrained Th2 cell-driven inflammation after allergen exposure. This indicated that ILC2- T_reg interactions were important for locally controlling Th2 cells. Mechanistically, we discovered that Gata3^high T_regs 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

Stephanie Flores Managing Director

ICIS Co-Managing Director Supports the leadership and governance of the Society and represents the organization. Works with the Governing Council to set and implement the strategic direction and ensure the organization meets its objectives. It is also my responsibility to ensure compliance with the Society's bylaws, policies and all applicable regulations.

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