SOCS3 regulates graft-versus-host disease

Abstract

Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3 ؊/⌬vav donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3 ؊/⌬LysM and SOCS3 ؊/⌬lck donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3 ؊/⌬lck donor T cells underwent enhanced alloantigendependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-␥ (IFN␥) after SCT. The enhanced capacity of the SOCS3 ؊/⌬lck donor T cell to induce acute GVHD was dependent on IFN␥ but independent of IL-10 or IL-17. Surprisingly, SOCS3 ؊/⌬lck donor T cells also induced severe, transforming growth factor ␤-and IFN␥-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD. (Blood. 2010;116(2): 287-296)

Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects

“…15,32,34 This dual expression has been attributed to epigenetic suppression of the regulatory protein SOCS3, 32 whose absence in donor T cells we have shown to also result in polyfunctional T-cell responses and exacerbated GVHD. 44 In this study, we found that Socs3 gene expression was downregulated in CD8 Table 3). These data suggest that differential expression of Socs3 may also drive the hyperproinflammatory T-cell phenotype observed in iTc17.…”

Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein

“…The molecular mechanism for this is unknown. Furthermore, genetic deletion of SOCS3, the endogenous negative regulator of STAT3, exacerbates graft versus host disease, a model of SSc (23).…”

Smg1 haploinsufficiency predisposes to tumor formation and inflammation

“…Measurement of serum cytokines levels was performed using cytokine bead array as described previously (39). Staining for cell surface markers was also performed as described previously (40,41).…”