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

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 CD8T 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 CD8T 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 CD8T cells correlates with reduced aGVHD incidence. Together, our findings identify SOCS1 as a predictive biomarker and a potential therapeutic target for personalized aGVHD prophylaxis.