Figure 1.

Roles of unconventional lymphocytes in intestinal repair. Gut ILC1 can produce MMP9 and TGFβ1 which contribute to extracellular matrix remodeling- a crucial part of repair. ILC2s become activated after exposure to IL-33 released by damaged epithelium, which results in their production of IL-13, which contributes to extracellular matrix remodeling and epithelial cell proliferation. Activated intestinal ILC2 also produce Areg which both enhances mucin production by epithelial cells increasing the mucus layer, and upregulates Claudin-1, increasing tight junction strength and reinforcing the barrier. Gut γδ T cells, or γδ IELs, can contribute to repair by the production of KGF which promotes epithelial proliferation, and via the production of AMPs such as RegIIIγ. In gut, the contribution of MAIT cells to healing responses remains relatively unknown, however these cells have been observed to respond similarly to human peripheral blood MAIT and can strengthen epithelial barrier integrity by inducing the tight junction protein, occludin, and by enhancing mucin expression to bolster the mucus layer. Intestinal ILC3s can become activated by PGE₂, SCFAs, or IL-23 and IL-1β. Activated ILC3s produce IL-22 which promotes epithelial stem cell maintenance in a STAT3 dependent manner, and can also promote the DNA damage response. ILC3s can also promote epithelial cell proliferation via a Hippo/Yap-1 pathway downstream of gp130. The factors released by ILC3s which signal via gp130 are not known, but may be IL-6, Lif or Oncostatin M as these all signal via gp130-coupled receptors. Activated ILC3s also produce GM-CSF which contributes to M1 polarization of macrophages which inhibit healing, but also inhibit fibrosis which is associated with scar formation. ILC3s can produce IL-22 and IL-17 which promotes the production of AMPs and mucins by epithelial cells, but it is not known if these cells are the key producers of these cytokines in this context. Created with BioRender.com.