# ETV1 Drives CD4+ T Cell‐Mediated Intestinal Inflammation in Inflammatory Bowel Disease Through Amino Acid Transporter Slc7a5

## TL;DR

This study shows that the ETV1 protein promotes harmful T cell activity in inflammatory bowel disease by boosting amino acid transport, offering a new treatment target.

## Contribution

The study identifies ETV1 as a novel driver of CD4+ T cell dysfunction in IBD through its regulation of the amino acid transporter SLC7A5.

## Key findings

- ETV1 is upregulated in IBD patients and correlates with disease severity.
- ETV1 deficiency reduces CD4+ T cell activation and Th17 differentiation, ameliorating colitis.
- ETV1 enhances SLC7A5 expression, which fuels T cell pathogenicity; blocking SLC7A5 reduces colitis.

## Abstract

Excessive CD4+ T cell responses drive inflammatory bowel disease (IBD), yet the transcriptional mechanisms underlying their dysfunction remain incompletely understood. Here, it is demonstrated that E‐twenty‐six variant transcription factor 1 (ETV1) is upregulated in IBD patients and positively correlates with disease severity. Etv1 deficiency impairs CD4+ T cell activation, proliferation, and T helper 17 (Th17) cell differentiation, thereby ameliorating TNBS‐induced colitis. Moreover, Etv1 deficiency attenuates CD45RBhighCD4+ T cell‐induced colitis, characterized by a reduction in pathogenic CD4+ T cells in the intestinal mucosa. Pharmacological inhibition of ETV1 ameliorates colitis in recombination activating gene 1‐deficient mice and suppresses human IBD T cell responses ex vivo. Mechanistically, Etv1 binds to the promoter of the gene encoding the amino acid transporter solute carrier family 7 member 5 (Slc7a5), enhancing its expression and subsequent amino acid uptake to fuel T cell pathogenicity. Restoring Slc7a5 expression rescues the proliferation, differentiation, and colitogenic function of Etv1‐deficient CD4⁺ T cells. Clinically, SLC7A5 is upregulated in IBD, and its blockade ameliorates T cell‐driven colitis in vivo. Collectively, the results establish a critical role for the ETV1‐Slc7a5 axis in driving pathogenic CD4⁺ T cell responses in IBD, highlighting this pathway as a novel therapeutic target.

This study identifies the transcription factor ETV1 as a key driver of CD4⁺ T cell‐mediated intestinal inflammation in inflammatory bowel disease (IBD). ETV1 promotes CD4⁺ T cell activation, proliferation, and Th17 differentiation by activating the amino acid transporter SLC7A5, fueling metabolic reprogramming. Inhibition of the ETV1‐SLC7A5 axis ameliorates CD4⁺ T cell‐mediated colitis, highlighting its therapeutic potential.