Distinct role in tissue repair

Credit: S.Bradbrook/NPG

Regulatory T (T_Reg) cells have a central role in maintaining immune tolerance through multiple mechanisms. They have also been shown to indirectly limit inflammation-induced tissue damage. But do T_Reg cells have a direct role in tissue protection? Reporting in Cell, Rudensky and colleagues show that, through the production of amphiregulin, T_Reg cells have a direct and non-redundant role in tissue repair and maintenance during infection that is independent of their suppressive activity and is induced by different cues.

Previous studies have shown that tissue-resident T_Reg cells can produce amphiregulin (which is encoded by AREG): a molecule produced by several cell types — including some activated immune cell populations — that has a role in organ development and promotes tissue repair under inflammatory conditions. To determine the exact role of T_Reg cell-derived amphiregulin, Arpaia et al. generated knockout mice in which Areg expression was specifically ablated in FOXP3⁺ T_Reg cells (Areg^fl/flFoxp3^YFP-Cre mice). These mice developed normally, showed normal lymphocyte differentiation and did not develop autoimmune disease. Further in vitro and adoptive transfer studies confirmed that loss of amphiregulin expression by T_Reg cells does not affect their suppressive functions.

To determine the role of T_Reg cell-derived amphiregulin in the context of infection and tissue damage, the authors moved to a model of influenza virus infection. Lung-resident T_Reg cells were shown to be the main source of amphiregulin early during the infection. Antiviral CD4⁺ and CD8⁺ T cell responses, as well as viral loads, were similar in infected Areg^fl/flFoxp3^YFP-Cre mice and control mice. However, compared with control mice, Areg^fl/flFoxp3^YFP-Cre mice showed a rapid decline in lung function and an increase in the severity and extent of lung tissue damage, with loss of barrier integrity and diffusion of viral proteins into the lung parenchyma. These data indicate that amphiregulin produced specifically by tissue-resident T_Reg cells has a key role in protecting against tissue damage and maintaining barrier integrity during virus-induced inflammatory responses in the lungs.

the tissue-repair functions of T_Reg cells are evoked in an 'innate' manner by IL-18 and IL-33

Next, the authors assessed whether the signals that promote the tissue-protective functions of T_Reg cells are the same as or distinct from the T cell receptor (TCR)-dependent signals that induce their suppressive functions. The pro-inflammatory cytokine interleukin-18 (IL-18) and the alarmin IL-33, expression of which is associated with inflammation and tissue damage, both induced amphiregulin production by T_Reg cells in vitro independently of TCR stimulation. Following influenza virus infection, ~80% of amphiregulin-expressing T_Reg cells expressed the IL-18 receptor (IL-18R) and ~30% of T_Reg cells expressed both amphiregulin and the IL-33 receptor ST2, with the majority of these co-expressing IL-18R. Furthermore, TCR-deficient T_Reg cells isolated from mice following influenza virus infection produced amphiregulin ex vivo. These data indicate that the tissue-repair functions of T_Reg cells are evoked in an 'innate' manner by IL-18 and IL-33 and are independent of TCR signalling.

Other studies have shown that T_Reg cells isolated from injured skeletal muscle, adipose tissue and inflamed gut tissue can express ST2, IL-18R and amphiregulin, suggesting that 'repair' T_Reg cells may exist at multiple tissue sites.