SOCS1: Regulator of T Cells in Autoimmunity and Cancer

Abstract

SOCS1 is a negative feedback regulator of cytokine and growth factor receptor signaling, and plays an indispensable role in attenuating interferon gamma signaling. Studies on SOCS1-deficient mice have established a crucial role for SOCS1 in regulating CD8 T cell homeostasis. In the thymus, SOCS1 prevents thymocytes that had failed positive selection from surviving and expanding, ensures negative selection and prevents inappropriate developmental skewing toward the CD8 lineage. In the periphery, SOCS1 not only controls production of T cell stimulatory cytokines but also attenuates the sensitivity of CD8 T cells to synergistic cytokine stimulation and antigen non-specific activation. As cytokine stimulation of CD8 T lymphocytes increases their sensitivity to low affinity TCR ligands, SOCS1 likely contributes to peripheral T cell tolerance by putting brakes on aberrant T cell activation driven by inflammatory cytokines. In addition, SOCS1 is critical to maintain the stability of T regulatory cells and control their plasticity to become pathogenic Th17 and Th1 cells under the harmful influence of inflammatory cytokines. SOCS1 also regulates T cell activation by dendritic cells via modulating their generation, maturation, antigen presentation, costimulatory signaling, and cytokine production. The above control mechanisms of SOCS1 on T cells, T regulatory cells and dendritic cells collectively contribute to immunological tolerance and prevent autoimmune manifestation. On other hand, silencing SOCS1 in dendritic cells or CD8 T cells stimulates efficient antitumor immunity. Thus, even though SOCS1 is not a cell surface checkpoint inhibitor, its regulatory functions on T cell responses qualify SOCS1as a "non-classical" checkpoint blocker. SOCS1 also functions as a tumor suppressor in cancer cells by regulating oncogenic signal transduction pathways. The loss of SOCS1 expression observed in many tumors may have an impact on classical checkpoint pathways. The potential to exploit SOCS1 to treat inflammatory/autoimmune diseases and elicit antitumor immunity is discussed.

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

“…Targeting SOCS1 , a negative regulator of JAK/STAT signaling in T cells, showed enhanced T cell clearance comparable to CBLB (Liau et al, 2018). Ablation of TCEB2, a binding partner of SOCS1, also improved tumor clearance, suggesting that the SOCS1/TCEB2 complex restrains T cell responses and is a potential target for immunotherapy (Ilangumaran et al, 2017; Kamizono et al, 2001; Liau et al, 2018). RASA2 , a GTPase-activating protein that stimulates the GTPase activity of wild-type RAS (Arafeh et al, 2015), has not been studied in the context of primary T cells and the immune system, but our findings suggest it may be a modulator of T cell proliferation, activation, and anti-tumor immunity.…”

Bioinformatic analyses and experimental validation of the role of m6A RNA methylation regulators in progression and prognosis of adrenocortical carcinoma

“…Type II interferons (IFN) can activate antitumor M1 Macrophages when it combined with TLR (toll-like receptor) stimulation [ 51 ]. CCR (cytokine-cytokine receptor) [ 52 ] and T lymphocytes (T cell co-inhibition and -stimulation) are also involved in anti-tumor immunity mediated by some stimulatory cytokines [ 53 ]. As a result, deactivation of these immune pathways is commonly undesirable for antitumor process.…”

Spatial Multiomics Analysis Identifies SOCS1 as a Key Immune Checkpoint in T cell Tolerance Induction of HSCT

“…The methodologies developed here might have important implications for addressing immunological pro les, such as those of dendritic cells and B cells, in other contexts of tolerance induction 9 as well as in cellular therapy. SOCS1 belongs to classic negative feedback inhibitor family and plays an indispensable role in attenuating IFN-γ signaling 23,24 . Consistent with previous studies, we also found Socs1 cKO mice showed aberrant CD4/CD8 ratio, which is indicated Socs1 involved in T-cell development in the thymus 25,26 .…”

“…attenuating IFN-γ signaling 23,24 . Consistent with previous studies, we also found Socs1 cKO mice showed aberrant CD4/CD8 ratio, which is indicated Socs1 involved in T-cell development in the thymus 25,26 .…”