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

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.