Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease, mediated by aberrantly activated CD4 T cells.  Notably, suppressor of cytokine signaling-1 (SOCS1) regulates CD4 T cell activation. In addition, SOCS1^+/- (SOCS1 deficient) mice develop lupus-like disease. Although murine studies implicate a relationship between decreased SOCS1 expression and increased lupus pathology, the ability to translate these animal findings to human disease has not been established. Therefore, the goals of this study were to (a) establish clinical relevance for SOCS1 deficiency in regard to human SLE and (b) establish the mechanism by which SOCS1 deficiency can lead to lupus development. 

Methods: Human: qPCR was performed on PBMCs isolated from SLE patients (n=20) and healthy controls (HCs) (n=8) to assess SOCS1 expression, relative to GAPDH. SOCS1 expression was correlated with indicators of disease activity (monocyte CD64 MFI and C3 levels). Mouse: SOCS1^+/- mice were studied prior to the onset of lupus disease. C57BL/6 mice served as wild-type (WT) controls. Naïve CD4⁺CD25^– T cells, isolated from spleen and LNs, were stimulated with anti-CD3 and anti-CD28 antibodies or only anti-CD3 antibody, with or without SOCS-1 KIR (mimetic peptide of SOCS1). Activation was assessed by flow cytometric analysis of CD25 and CD69. CFSE staining and ³H Thymidine incorporation were employed to measure proliferation. Akt activation was measured by western blotting. For statistical comparisons between SLE patients and HCs and between SOCS1^+/- and WT, the Mann-Whitney U test was performed. Spearman’s correlation was used for correlation data.

Results: Similar to murine models of disease, SLE patients’ PBMCs had reduced expression of SOCS1 in comparison to HCs. Additionally, SOCS1 expression was negatively correlated with monocyte CD64 expression and positively correlated with C3 levels. Mechanistic data revealed that stimulating SOCS1^+/- naïve CD4 T cells with anti-CD3 antibody alone resulted in an elevated population of CD69 and CD25 expressing cells. In parallel with the elevated population of activated cells under this suboptimal T cell activation condition, these SOCS1 deficient cells also displayed enhanced ³H thymidine incorporation and an increased CFSE^low population – indicative of increased proliferation.  The enhanced activation and proliferation was not due to an elevated population of memory T cells, but rather to a reduced requirement for Akt activation. Notably, SOCS1-KIR reduced the abnormal activation and proliferation.

Conclusion:  SOCS1 deficiency is clinically relevant to human SLE. We also determined that SOCS1 deficient CD4 T cells do not require CD28-costimulation in order to undergo activation and proliferation. This has significant implications for lupus development, as SOCS1 deficient autoreactive T cells that have a reduced threshold for activation can activate autoreactive B cells, which can perpetuate disease. Significantly, SOCS1-KIR has the capacity to restore the proper T cell activation threshold. Based on this data, we propose that SOCS1-KIR should begin to be explored as a potential candidate for the prevention/treatment of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulation-of-aberrant-cd4-t-cell-activation-by-suppressor-of-cytokine-signaling-1-socs1-mimetic-peptide-has-relevance-to-human-systemic-lupus-erythematosus/