Investigating Novel αVβ8 integrin mediated Transcriptional Events in Murine Dendritic Cells and Regulatory T-cells

Abstract

The heterodimeric integrin receptor αVβ8 is expressed by both CD103+ dendritic cells (DCs) and regulatory T-cells (Tregs). Its main function is to activate the latent form of the anti-inflammatory cytokine Transforming Growth Factor β (TGFβ) via the removal of the Latency Associated Peptide (LAP). Loss of αVβ8 integrin on murine DCs results in age-related autoimmunity and spontaneous development of colitis. Loss of αVβ8 integrin on Tregs attenuated their ability to suppress effector T-cell responses during ongoing inflammation. Integrins initiate intracellular signalling cascades following binding of their ligand, yet little is known about the intracellular effects of αVβ8 integrin ligation and how this may contribute to its role in immune regulation. We aimed to use RNA-sequencing analysis to elucidate potential novel αVβ8 mediated transcriptional changes within primary murine DCs and Tregs after incubation with LAP. We found that LAP incubation resulted in the significant upregulation and downregulation of 41 protein-coding genes in DCs and 164 protein-coding genes in Tregs. Importantly, these genes were not significantly altered in DCs or Tregs lacking the αVβ8 integrin and may therefore be altered due to LAP-αVβ8-mediated signalling. We also found that over a quarter of the total genes in DCs lacking αVβ8 integrin were significantly altered compared to wild-type (WT) DCs, whereas 199 genes in Tregs lacking αVβ8 integrin were significantly altered compared to WT Tregs. These data can be used as a platform upon which to base further experiments to identify potential novel functional mechanisms of αVβ8 integrin, enabling the identification of potential therapeutic targets to restore and promote immune tolerance via the αVβ8-TGFβ pathway.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Supervisor) & Daniel Davis (Supervisor)