# Loss of SOCS1 in Donor T Cells Exacerbates Intestinal GVHD by Driving a Chemokine‐Dependent Pro‐Inflammatory Immune Microenvironment

## TL;DR

Loss of SOCS1 in donor T cells worsens intestinal GVHD by creating a pro-inflammatory environment, and targeting this pathway could help prevent the disease.

## Contribution

This study reveals SOCS1 as a key regulator of GVHD and identifies it as a potential biomarker and therapeutic target.

## Key findings

- Socs1 loss in T cells drives pro-inflammatory differentiation, especially in CD8+ T cells.
- Socs1 deficiency activates STAT1/2, leading to Ccl5 expression and M1 macrophage polarization.
- High SOCS1 expression in CD8+ T cells correlates with reduced aGVHD incidence in patients.

## Abstract

Acute graft‐versus‐host disease (aGVHD) of the gastrointestinal tract is a frequent and often fatal complication of allogeneic hematopoietic stem cell transplantation. Suppressor of Cytokine Signaling 1 (SOCS1) is a key regulator of T cell pathogenicity, yet its role in aGVHD remains unclear. Using T cell‐specific Socs1 knockout models, we show that Socs1 loss intrinsically drives pro‐inflammatory T cell differentiation independent of antigen stimulation, with the strongest effects observed in CD8+ T cells. Mechanistically, Socs1 deficiency activates a STAT1/2‐dependent transcriptional program, inducing Ccl5 expression, monocyte recruitment, and M1‐like macrophage polarization in peripheral lymphoid organs at steady state. After transplantation, Socs1‐deficient T cells display enhanced infiltration into intestinal crypts, accompanied by increased CD8+ T cell effector function, monocyte accumulation, and inflammatory macrophage polarization in target tissues. These changes promote tissue injury and impair regeneration, resulting in lethal aGVHD. Importantly, JAK1/2 inhibition with ruxolitinib reverses these pathogenic effects. Clinically, high SOCS1 expression in donor‐derived CD8+ T cells correlates with reduced aGVHD incidence. Together, our findings identify SOCS1 as a predictive biomarker and a potential therapeutic target for personalized aGVHD prophylaxis.

T cell‐specific Socs1 knockout leads to inflammatory differentiation of CD8+ T cells, prompting the STAT1/2 complex to drive the activation of Ccl5, Ccr5, and Cxcr3, and promoting the skewing of monocytes toward a pro‐inflammatory M1 macrophage lineage. After transplantation, Socs1‐deficient CD8+ T cells infiltrate the intestine and orchestrate a vicious inflammatory cycle by recruiting monocytes via CCL5 secretion, thereby sustaining crypt‐localized inflammation and exacerbating intestinal injury during aGVHD. Although a CCL5‐neutralizing antibody, Maraviroc, and Ruxolitinib all alleviate intestinal GVHD in Socs1‐deficient models, Ruxolitinib demonstrates superior efficacy. Clinically, high SOCS1 expression in CD8+ T cells correlates with reduced aGVHD incidence following allo‐HSCT.