Abstract
Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.
Highlights
Abbreviations autoimmune lymphoproliferative syndrome (ALPS) Autoimmune lymphoproliferative syndrome CD Cluster of differentiation IFN Interferon janus kinase (JAK) Janus kinase kinase inhibitory region (KIR) Kinase inhibitory region lymph nodes (LN) Lymph node MHC Major histocompatibility complex systemic lupus erythematosus (SLE) Systemic lupus erythematosus Suppressor of Cytokine Signaling-1 (SOCS1) Suppressor of cytokine signaling signal transducers and activators of transcription (STAT) Signal transducer and activator of transcription TLR Toll-like receptor Treg Regulatory T cells
To assess the ability of SOCS1 mimetic peptides (SOCS1-KIR) to modulate T lymphocyte activation, we cultured a single cell suspension from total axillary, brachial, cervical, and inguinal LN isolated from 8-week old MRL/lpr mice with anti-CD3 or anti-CD3/anti-CD28 antibodies, in the presence of SOCS1
As a control, activated cultures were incubated with a peptide corresponding to the region of JAK2 previously shown to interact with endogenous SOCS1 thereby acting as a SOCS1 antagonist44. anti-CD3 stimulation yielded a modest upregulation of CD25, CD69, and CD44 in CD4+ (Fig. 1A–C) and CD8+ (Fig. 1D–F) T lymphocytes
Summary
Abbreviations ALPS Autoimmune lymphoproliferative syndrome CD Cluster of differentiation IFN Interferon JAK Janus kinase KIR Kinase inhibitory region LN Lymph node MHC Major histocompatibility complex SLE Systemic lupus erythematosus SOCS1 Suppressor of cytokine signaling STAT Signal transducer and activator of transcription TLR Toll-like receptor Treg Regulatory T cells. Autoimmune diseases such as systemic lupus erythematosus (SLE) are often debilitating, polygenic, and present with varied clinical manifestations[1]. These data suggest that therapeutic targeting of the SOCS1 pathway, through the use of peptides that mimic SOCS1 activity, may serve as a novel approach for the treatment of lymphocyte mediated autoimmunity
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