Date: Sunday, November 8, 2015
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
The interplay between effector and regulatory T cells (Tregs) is a key element among peripheral tolerance mechanisms in Systemic Lupus Erythematosus (SLE). Resistance to suppression has been acknowledged as part of the defects shown by lupus T cells. The E3 ligase Cbl-b has been shown to modulate T cell unresponsiveness in SLE. However its role in peripheral Tregs tolerance has not been addressed. The aim of this study was to assess Cbl-b expression and its relationship to the resistance to suppression phenotype, as well as the ubiquitination profile in SLE.
We included 30 SLE patients (20 with active disease and 10 with clinical remission) and 30 age and gender matched healthy controls. Peripheral blood mononuclear cells were isolated by density-gradient sedimentation. Effector (CD4+CD25–) and Tregs (CD4+CD25+CD127–) were purified by magnetic selection. The expression of Cbl-b and the ubiquitination profile were analyzed by western blot. Proliferative responses were assessed in allogeneic and autologous cocultures by CFSE method. Differences were assessed by t Student test. p<0.05 was considered as statistically significant.
We found decreased Cbl-b expression in Tregs from SLE patients in comparison to healthy controls (1.1±0.9 vs 2.5±1.8+6, p=0.003), which was associated with resistance to suppression in proliferation assays (r=0.633, p=0.039). This phenomenon was related to a differential polyubiquitination profile characterized by deficient expression of Lys63 (K63) substrates in regulatory T cells from SLE patients when compared to healthy controls. We analyzed different signaling molecules that are prone to K63 regulation and found increased expression of phosphorylated STAT3 (pSTAT3) in T cells from SLE patients in comparison to healthy controls.
Conclusion: Our data suggest that Cbl-b is able to regulate the interplay between effector and Tregs, particularly, the resistance to suppression by regulating the K63 polyubiquitination profile in T cells from SLE patients. Moreover, deficient K63 polyubiquitination mainly of STAT3 is associated to the enhanced pSTAT3 expression and might play a role in the maintenance of resistance to suppression in SLE, as has been previously reported for other autoimmune diseases.
To cite this abstract in AMA style:Gómez-Martín D, Alcocer-Varela J, Romo-Tena J, Barrera-Vargas A, Merayo-Chalico J. Lys63-Polyubiquitination By the E3 Ligase Casitas B-Lineage Lymphoma-b Modulates Peripheral Regulatory T Cell Tolerance in Patients with Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/lys63-polyubiquitination-by-the-e3-ligase-casitas-b-lineage-lymphoma-b-modulates-peripheral-regulatory-t-cell-tolerance-in-patients-with-systemic-lupus-erythematosus/. Accessed June 4, 2020.
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