Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
T-cell resilience is critical to the immune pathogenesis of human autoimmune arthritis. Autophagy is essential for memory T cell generation and is associated with pathogenesis in rheumatoid arthritis (RA). We have previously described that CD4+ T cells in patients with RA have an increased level of autophagy compared to their healthy controls. Here, we sought to explore at epigenetic and transcriptional levels the concept of persisting increased autophagy as the consequence of “autophagic memory”, as one of the mechanisms conferring resilience to pathogenic T cells, in particular to a subset of CD4+ T cells (CPL: Circulating Pathogenic-like Lymphocytes), which are significantly more represented in patients with active arthritis and patients resistant to therapy with biologics.
Autophagy was assessed in CD4+ T cell subsets from autoimmune arthritis patients and healthy subjects using flow cytometry. RNA sequencing and methylation array analysis to understand the molecular mechanism of autophagic memory. Transcription-factor gene regulatory network analysis was built to identify key regulators. qPCR was used to confirm the gene expression level of key regulators.
We demonstrated “Autophagic memory” as elevated autophagy levels in CD4+ memory T cells compared to CD4+ naive T cells and in Jurkat Human T cell line trained with starvation stress. We then showed increased levels of autophagy in pathogenic CD4+ T cells subsets from autoimmune arthritis patients. Using RNA-sequencing, transcription factor gene regulatory network and methylation analyses we identified MYC as a key regulator of autophagic memory. We validated MYC levels using qPCR and further demonstrated that inhibiting MYC increased autophagy.
The present study proposes the novel concept of autophagic memory and suggests that autophagic memory confers metabolic advantage to pathogenic T cells from RA and supports its resilience and long term survival. Particularly, suppression of MYC imparted the heightened autophagy levels in pathogenic T cells. These studies have a direct translational valency as they identify autophagy and its metabolic controllers as a novel therapeutic target.
To cite this abstract in AMA style:Kumar P, Leong JY, Paleja B, Saidin S, van Loosdregt J, Arkachaisri T, Consolaro A, Gattorno M, Martini A, W Williams G, D Pischel K, Lotz M, Albani S. Molecular Mechanisms of Pathogenic T Cell Resilience in Human Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/molecular-mechanisms-of-pathogenic-t-cell-resilience-in-human-arthritis/. Accessed June 6, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-mechanisms-of-pathogenic-t-cell-resilience-in-human-arthritis/