Mucosal Immunology | 警告分子IL-1和IL-33在黏膜炎症过程中调节Foxp3...

Paper Reading

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Thealarmins IL-1 and IL-33 differentially regulate the functional specialisation of Foxp3+ regulatory T cells during mucosal inflammation

Fernando Alvarez, Roman Istomine,Mitra Shourian,...Salman Qureshi, Jörg H. Fritzand Ciriaco A.Piccirillo et al.

Mucosal Immunology (2019) 12:746–760

The exposure to environmental stimuli causes mucosal surfaces to develop local mechanisms to maintain homeostasis at steady-state conditions, all-the-while mounting strong immune responses when required. CD4⁺Foxp3⁺regulatory T (TREG) cells are critical mediators of peripheral immune self-tolerance and modulators of immune responses directed towards a spectrum of self and non-self antigens.Foxp3 is a lineage-specifying transcription factor essential for the development and function of T_REG cells. Induction and sustained expression of Foxp3 defines the core transcriptional program of T_REGcells, establishing their phenotype and suppressive function, as well as regulating key cell-intrinsic, homeostatic processes, including cytokine signaling pathways. The stability of Foxp3 expression and T_REG cell function is a dynamic process dictated by the inflammatory environment. Inflammatory cues can modulate the epigenetic and transcriptional landscape ofFoxp3+ T_REG cells, forcing them to specialize their functions for a context-dependent adaptation to evolving immune responses.

By applying an unbiased screen to uncover the mechanistic events leading to a downregulation of Foxp3 expression in T_REG cells, the authors identify a unique role of the IL-1 family of cytokines in modulating there programming potential of T_REG cells during inflammation. They show that cell surface expression of the IL-33R (ST2,I l1rl1) identifies a subset of functionally stable Helios⁺Foxp3⁺T_REG cells that are resistant to plasticity and loss of suppressive function, whereas IL1R1 (Il1r1)expression identifies RORγT⁺ Helios⁻ T_REGcells that acquire a Th17 cell phenotype and fail to suppress. While a Th17polarizing milieu induces IL-1R1 expression on T_REG cells, IL-33 favours the stability of the Helios⁺ST2⁺ T_REG cell phenotype in similar conditions. Importantly, ST2⁺ T_REG cells accumulate early in the lungs upon infection with influenza virus or the fungal pathogen Cryptococcus neoformans, and segregates suppressive from inflammatory TREG cells throughout the course of infection. Abrogation of IL-33, but not IL-1 signaling, in T_REG cells compromises their suppressive function and fuels inflammatory responses in vivo. Importantly, lack of IL-1 signalling alters the dynamics of ST2⁺and RORγT⁺ Foxp3⁺ T_REG populations in the lung, and augments susceptibility to fungal infection. Overall, they show that IL-1 and IL-33 exert opposite roles in controlling the adaptation and functional specialisation of Foxp3⁺ T_REG cells at mucosal surfaces.

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Innate Control of Tissue-Reparative Human Regulatory T Cells

Avery J. Lam,KatherineN. MacDonald,Anne M. …Sachdev S. Sidhu,John D. Rioux,and Megan K. Levings et al.

The Journal of Immunology, 2019, 202:2195–2209.

Tregs normally suppress the activation and effector function of other immune cells to maintain self-tolerance and homeostasis, and adoptive transfer of ex vivo-expanded Tregs has been found to be safe and potentially efficacious in clinical trials for graft-versus-host disease and type 1 diabetes. Although the majority of research on Treg biology to date has centered on their immunosuppressive potential, there has been an increasing appreciation for the nonimmune functions of Tregs, particularly in tissue-specific contexts. Several reports in mice have shown that Tregs participate in tissue repair. In models of muscle and skin injury, Tregs indirectly facilitate wound healing by limiting IFN-γ production and promoting anti-inflammatory myeloid cells. MouseTregs also act directly on parenchymal cells to drive repair: muscle- and lung-infiltrating Tregs mediate muscle and lung repair after injury or influenza infection, respectively, via production of amphiregulin (AREG), alow-affinity EGFR ligand. In muscles, AREG induces satellite cell differentiation in vitro, and its administration to injured mice improves muscle repair. In a model of influenza-induced lung damage, the early production of Treg-derived AREG was found to be critical for normal tissue repair.

In this study, the authors aimed to answer the outstanding question of whether human Tregs have a similar tissue repair potential. There are limited data on whether human ST2⁺ Tregs are present in various tissues. Also unknown is whether human Tregs have the potential to produce AREG in response to IL-33 or other factors, although human CD4⁺ T cells have been described to produce AREG in response to TCR activation. They show that human Tregs in blood and multiple tissue types produced amphiregulin, but this was neither a unique feature of Tregs nor selectively upregulated in tissues. HumanTregs in blood, tonsil, synovial fluid, colon, and lung tissues did not expressST2, so ST2⁺ Tregs were engineered via lentiviral-mediated overexpression, and their therapeutic potential for cell therapy was examined. Engineered ST2⁺ Tregs exhibited TCR-independent, IL-33-stimulated amphiregulin expression and a heightened ability to induce M2-like macrophages. The finding that amphiregulin-producing Tregs have a noneffector phenotype and are progressively lost upon TCR-induced proliferation and differentiation suggests that the tissue repair capacity of human Tregs may be an innate function that operates independently from their classical suppressive function.

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