Postdoctoral Fellow Hanyang University, Seoul Seongdong-gu, United States
Introduction/Rationale: Conventional CD4 T cell activation requires antigen recognition through the T cell receptor along with co-stimulatory signals and cytokines. Recent studies have demonstrated that cytokine signaling alone can activate CD4 T cells without antigen recognition, called bystander activation, and these CD4 T cells contribute to various inflammatory diseases. However, whether these bystander activated CD4 T cells contribute to pulmonary fibrosis remains unclear.
Methods: In this study, we investigated the unique function of fibrotic CD4 T cells using bleomycin-induced lung fibrosis model and analysis of public single-cell and spatial RNA sequencing data from lung tissue of human IPF patients, and explored the underlying mechanisms.
Results: We identified a subpopulation of PD-1high CD4 T cells which are markedly increased in pulmonary fibrosis mouse model and in lung tissue from IPF patients. These cells mainly express IL-33 receptor and amphiregulin and their activation is independent of specific antigen. Notably, PD-1high CD4 T cells are already present in lung tissue of steady-state mice, increased with aging and respond selectively to IL-33 and IL-25 stimulation in the absence of TCR engagement. Single-cell RNA sequencing revealed that IL-33 and IL-25 stimulated CD4 T cells upregulate Th2-related cytokines and amphiregulin with Batf identified as a key transcriptional regulator of this bystander response. Batf deficiency and chemical inhibition of Batf significantly reduced bystander-activation of CD4 T cells by IL-33 and IL-25 stimulation and markedly attenuated pulmonary fibrosis pathology.
Conclusion: Taken together, these findings identify a unrecognized population of bystander-activated, profibrotic PD-1high CD4 T cells in both mice and humans and establish the Batf/amphiregulin axis in CD4 T cells as an important mediator of pulmonary fibrosis progression.
