Immune and non-immune mediated roles of regulatory T-cells during wound healing

The immune system has a well-established contribution to tissue homeostasis and wound healing. However, in many cases immune responses themselves can cause severe tissue damage. Thus, the question arose to which extent cells of the immune system directly contribute to the process of wound healing and to which extent the resolution of excessive immune responses may indirectly contribute to wound healing. FoxP3 expressing CD4 Tcells, so-called regulatory T-cells (T_regs), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that T_regs next to an immune regulatory, “damage-limiting” function may also have an immune independent, “damageresolving” direct role in wound healing. In particular, the release of the EGF-like growth factor Amphiregulin by tissue-resident T_regs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bioactive TGFβ, a cytokine involved both in immune regulation as well as in the process of wound repair. In light of these findings, we discuss whether, by locally activating TGFβ, T_regderived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that T_reg-derived Amphiregulin in an autocrine way may enable an IL-33 mediated survival and expansion of tissue-resident T_regs upon injury. Furthermore, T_reg-derived Amphiregulin may contribute to a constitutive, low-level release of bio-active TGFβ within tissues, leading to continuous tissue regeneration and to an immune suppressive environment, which may keep inflammation prone tissues in an homeostatic state.