Date: Monday, November 6, 2017
Session Title: T Cell Biology and Targets in Autoimmune Disease Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Autophagy is central to many key immune related pathways, disregulation of which has been associated with rheumatoid arthritis (RA), cancer and neurodegenerative diseases. Autophagy is required for memory T cell generation and maintenance. Previous studies from our group showed higher levels of autophagy in CD4+ T cells from RA patients. Flow cytometry analysis of T cells from healthy individual indeed showed higher autophagy levels in memory CD4 and CD8 cells after activation, compared to naive T cells. However the basal level of autophagy was similar in both cell types, suggesting a memory for autophagy. Here, we hypothesise that T cells which experience immunological encounters and activation, attain, when compared to naive cells, heightened autophagic levels when a similar stimulus is encountered again, a phenomenon, which we term “autophagic memory” which may be pathogenically relevant.
To dissect the molecular mechanisms of autophagic memory, we trained human T cells in low serum medium, to elicit stress-induced activation, for 5 days. The cells were then cultured in 10% serum media for 100 generations and subjected to RNAseq and Methylome analyses at various time points. Primary cells from RA patients were sorted using flowcytometry followed by quantitative PCR analyses.
RNA-sequencing and methylome analysis of the trained and control cells at 5, 30,70 and 100 generations identified clusters of genes stably up or down regulated in trained cells compared to control cells until the 30th generation. These short term expression minor (STEM) gene expression profiles represented pathways related to stress, immunity and metabolism, all of which are critical contributors to the onset and modulation of the autophagic process. A transcription factor gene network reconstruction at the system level using ENCODE and HTrib data identified intersecting key regulatory genes for autophagic memory. Specifically, some key genes with roles in autophagy were also shown to be epigenetically modified in response to the starvation stimulus that was sustained over 30 generations suggesting a role for these genes in retention of autophagic memory. Importantly, gene expression analyses of primary CD4+T cells from RA patients recapitulated this observation, demonstrating a clinically relevant molecular signature that could contribute to autophagic memory in these cells.
We describe here epigenetic and transcriptional elements which determine and control persistence of autophagic memory in experienced T cells. Based on our data which are reproducible both in healthy and diseases samples, we suggest that autophagic memory is an integral part of efficient activation of memory T cells, and it also contributes to persistence of T cell mediated inflammation in autoimmunity.
To cite this abstract in AMA style:Kumar P, van Loosdregt J, Saidin S, Paleja B, Albani S. Autophagic Memory in Stress Experienced Human T Cells [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/autophagic-memory-in-stress-experienced-human-t-cells/. Accessed June 4, 2020.
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