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 T-cells, so-called regulatory T-cells (Tregs ), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that Tregs next to an immune-regulatory, 'damage-limiting' function may also have an immune-independent 'damage-resolving' direct role in wound healing. In particular, the release of the epidermal growth factor-like growth factor Amphiregulin by tissue-resident Tregs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bio-active transforming growth factor (TGF)β, 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, Treg -derived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that Treg -derived Amphiregulin in an autocrine way may enable an IL-33-mediated survival and expansion of tissue-resident Tregs upon injury. Furthermore, Treg -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.