MITOCHONDRIA LOCALIZED TLR ADAPTOR SARM IS PROAPOPTOTIC DURING T-CELL IMMUNE RESPONSE

Abstract

Following infection clearance, the expanded T cells are terminated to achieve homeostasis, failure of which results in lymphoproliferative and autoimmune diseases. We report that SARM, the most conserved TLR adaptor, is proapoptotic during T-cell contraction. SARM-knockdown T cells survived longer following influenza infection in vivo. During T-cell activation, the SARM level fell before rising, correlating inversely with T-cell proliferation and subsequent clearance. A similar drastic decrease in the level of SARM was observed during in vivo T-cell proliferation. Consistently SARM expression was reduced in NK/T lymphoma patients compared to healthy individuals. SARM-knockdown rescued T cells from both activation- and neglect-induced cell deaths. Mechanistically, SARM expression suppresses Bcl-xL and ERK phosphorylation. The N terminal 27 amino acids, specifically Arginine14 determine the mitochondrial localization of SARM. The mitochondria-localization is crucial for the intrinsic apoptosis mediated by SARM. Collectively, we show how SARM mediates apoptosis, which is crucial for T-cell contraction following infection.