NOD2 and TLR2 Signal via TBK1 and PI31 to Direct Cross-presentation and CD8 T Cell Responses [article]

Daniele Corridoni, Seiji Shiraishi, Thomas Chapman, Tessa Steevels, Daniele Muraro, Marie-Laetitia Thezenas, Gennaro Prota, Ji-Li Chen, Uzi Gileadi, Nicola Ternette, Vincenzo Cerundolo, Alison Simmons
2019 bioRxiv   pre-print
NOD2 and TLR2 recognize components of bacterial cell wall peptidoglycan and direct defense against enteric pathogens. CD8+ T cells are important for immunity to such pathogens but how NOD2 and TLR2 induce antigen specific CD8+ T cell responses is unknown. Here, we define how these pattern recognition receptors (PRRs) signal in primary dendritic cells (DCs) to influence MHC class I antigen presentation. We show NOD2 and TLR2 phosphorylate PI31 via TBK1 following activation in DCs. PI31 interacts
more » ... DCs. PI31 interacts with TBK1 and Sec16A at endoplasmic reticulum exit sites (ERES), which positively regulates MHC class I peptide loading and immunoproteasome stability. Following NOD2 and TLR2 stimulation, depletion of PI31 or inhibition of TBK1 activity in vivo impairs DC cross-presentation and CD8+ T cell activation. DCs from Crohn's patients expressing NOD2 polymorphisms show dysregulated cross-presentation and CD8+ T cell responses. Our findings reveal unidentified mechanisms that underlie CD8+ T cell responses to bacteria in health and in Crohn's.
doi:10.1101/570705 fatcat:fu5cryubrvdave7h2fefgs46ia