Molecular Mechanisms of Pathogenic T Cell Resilience in Human Arthritis

Pavanish Kumar¹, Jing Yao Leong¹, Bhairav Paleja¹, Suzan Saidin¹, jorg van Loosdregt¹, Thaschawee Arkachaisri², Alessandro Consolaro³, Marco Gattorno⁴, Alberto Martini⁵, Gary W Williams⁶, Ken D Pischel⁶, Martin Lotz⁷ and Salvatore Albani⁸, ¹Translational Immunology Institute, Singhealth/Duke-NUS Academic Medical Centre, Singapore, Singapore, ²KK Women's and Children's Hospital, Singapore, Singapore, ³Second Paediatric Division, University of Genoa and G Gaslini Institute, Genova, Italy, Genova, Italy, ⁴Second Paediatric Division, University of Genoa and G Gaslini Institute, Genova, Italy, Genoa, Italy, ⁵Pediatric Rheumatology International Trial Organization (PRINTO) Coordinating Centre, Genoa, Italy, ⁶Scripps Clinic, La Jolla,, California, CA, ⁷Department of Molecular & Experience Medicine, Scripps Research Institute, LaJolla, CA, ⁸Translational Immunology Institute, Singhealth/Duke-NUS Acedemic Medical Centre, Singapore, Singapore

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Autoimmunity, autophagy, inflammation and rheumatoid arthritis (RA), T cells

Session Information

Date: Sunday, October 21, 2018

Title: T Cell Biology and Targets in Autoimmune and Inflammatory Disease Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

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.

Methods:

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.

Results:

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.

Conclusion:

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.

Disclosure: P. Kumar, None; J. Y. Leong, None; B. Paleja, None; S. Saidin, None; J. van Loosdregt, None; T. Arkachaisri, None; A. Consolaro, None; M. Gattorno, None; A. Martini, None; G. W Williams, None; K. D Pischel, None; M. Lotz, None; S. Albani, None.

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 9). https://acrabstracts.org/abstract/molecular-mechanisms-of-pathogenic-t-cell-resilience-in-human-arthritis/. Accessed .

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