Type 2 lymphocytes restrict type 3 lymphocytes during liver fibrosis and colocalize in fibroblast niches

TL;DR

Type 2 lymphocytes limit harmful liver fibrosis by controlling type 3 lymphocytes and interacting with fibroblast niches.

Contribution

Discovery of spatial interactions between T2Ls, T3Ls, and fibroblasts in liver fibrosis regulation.

Findings

T2Ls, especially ILC2s, accumulate near T3Ls and fibroblasts in fibrotic liver areas.

Loss of T2Ls increases T3Ls and worsens liver fibrosis in mouse models.

Combined ablation of T2Ls and T3Ls reduces liver fibrosis.

Abstract

Fibroblasts are dynamic structural cells that direct both beneficial tissue repair and pathological organ fibrosis through interactions with tissue-resident type 2 lymphocytes (T2Ls) and type 3/17 lymphocytes (T3Ls). The cytokines interleukin-13 (IL-13) and IL-17A, produced by T2Ls and T3Ls, respectively, are linked to both tissue inflammation and fibrosis, but how their spatial positioning influences beneficial or pathological organ remodeling remains unclear. Using mouse models of liver injury and fibrosis, three-dimensional microscopy, and spatial transcriptomics, we found an accumulation of periportal and fibrotic tract T2Ls, predominantly group 2 innate lymphoid cells (ILC2s), positioned near T3Ls and niche adventitial fibroblasts and adjacent to discrete profibrotic myofibroblasts. Unexpectedly, T2L ablation worsened both carbon tetrachloride– and bile duct ligation–induced liver fibrosis, accompanied by increased IL-17A+ T3Ls, predominantly γδ T cells. In contrast, concurrent T2L and T3L ablation reduced liver fibrosis. Our work suggests a spatially associated cross-talk between liver lymphocytes and fibroblast niches that tunes liver repair but can go awry in pathological liver fibrosis.

T2Ls and T3Ls colocalize in liver fibroblast niches; T2L loss drives T3L expansion and worsens fibrosis.

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