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Immune Reprogramming

SIRT1 Model

The lab’s interest in this area started when we showed in 1996 that Tat hyperactivates HIV-infected T cells by amplifying signals through the CD28 coreceptor and NF-kappa B transcription factors. We later showed that Tat inhibits the NAD+-dependent deacetylase SIRT1 leading to hyperacetylation and hyperactivation of NF-kappa B. We have since further explored the immune regulatory role of SIRT1 and showed that it plays a critical role in the balance between immune suppressive regulatory T cells (Tregs) and pro-inflammatory Th17 cells by directly deacetylating the FoxP3 and RoR-gamma-t transcription factors. The control of Treg and Th17 responses is a key determinant of immune self-tolerance, and thus represents a vital front in the search for new therapies against autoimmunity. Recently, we identified the evolutionarily conserved SIRT1-FoxO1 axis as a regulator of resting human CD8+ memory T cell metabolism and cytotoxicity. Loss of SIRT1 leads to metabolic reprogramming and enhanced cytotoxicity in CD8+ T cells through proteasomal degradation of the forkhead transcription factor FoxO1. We are currently exploring this axis as a target to reprogram terminally differentiated memory T cells and delay the immune aging process. In addition, we are linking the known metabolic functions of SIRT1 and FoxO1 with T cell biology to develop new strategies to fight HIV infection.

Selected publications:

Jeng, M.Y., Hull, P.A., Fei, M., Kwon, H.-S., Tsou, C.-L., Kasler, H., Ng, C.-P., Gordon, D.E., Johnson, J., Krogan, N., Verdin, E., Ott, M., 2017. Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1. J Exp Med. doi:10.1084/jem.20161066;
in the press: National Science Foundation, Medical Xpress

Lim HW, Kang SG, Ryu JK, Schilling B, Fei M, Lee IS, Kehasse A, Shirakawa K, Yokoyama M, Schnolzer M, Kasler HG, Kwon H-S, Gibson BW, Sato H, Akassoglou K, Xiao C, Littman DR, Ott M, Verdin E (2015) SIRT1 deacetylates RORγt and enhances Th17 cell generation. J Exp Med 212:9

Kwon HS, Lim HW, Wu J, Schnolzer M, Verdin E, Ott M (2012) Three Novel Acetylation Sites in the Foxp3 Transcription Factor Regulate the Suppressive Activity of Regulatory T Cells. J Immunol 188:2712–2721. 

Kwon H-S, Ott M (2008) The ups and downs of SIRT1. Trends Biochem Sci 33:517–525. 

Kwon H-S, Brent MM, Getachew R, Jayakumar P, Chen L-F, Schnolzer M, McBurney MW, Marmorstein R, Greene WC, Ott M (2008) Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation. Cell Host Microbe 3:158–167

Pagans S, Pedal A, North BJ, Kaehlcke K, Marshall BL, Dorr A, Hetzer-Egger C, Henklein P, Frye R, McBurney MW, Hruby H, Jung M, Verdin E, Ott M (2005) SIRT1 Regulates HIV Transcription via Tat Deacetylation. Plos Biol 3:e41.