Williams Endowed Chair and Professor of Immunology and PathogenesisLab Homepage: http://mcb.berkeley.edu/labs/winoto/
Our lab is interested in the molecular mechanisms of cell death in the immune system in the context of autoimmunity, cancer and infectious diseases. We are using a combination of biochemical, molecular biological and mouse transgenic/gene targeting approaches in our studies.
T cell self-tolerance is thought to involve central tolerance (negative selection) involving apoptosis of autoreactive thymocytes and peripheral mechanism through regulatory T cells (Treg). The crucial role of peripheral tolerance has been demonstrated by the lethal autoimmune phenotype of Treg-less mice. In contrast, evidence supporting an essential role for negative selection has been lacking until recently. Bim, a BH3-only Bcl-2 family protein is essential for thymocyte apoptosis. However, its loss doesn’t result in multi-organ autoimmunity. Additional loss of Puma, also a BH3-only protein, can enhance the Bim-/- thymic deletion defects, leading to development of autoimmunity. However, the role of non-T cells in these mice cannot be excluded. Consistent with this, mice with T cell-specific expression of Bcl-2, capable of blocking multiple BH3-only proteins, are largely normal. In addition to Bim, the nuclear receptor Nur77 family members have also been implicated in negative selection. Nur77 family members might function to promote apoptosis by associating with Bcl-2, exposing the Bcl-2 potentially pro-apoptotic BH3 domain. We found that T cell-specific expression of a Bcl-2 BH3 mutant transgene (Bcl-2-BH3*), which can block all these apoptotic pathways, results in enhanced rescue of thymocytes from negative selection when compared to wild-type transgenic Bcl-2. Although Treg cell number is increased, aged Bcl-2-BH3* mutant mice progressively accumulate activated, autoreactive T cells, culminating in development of multi-organ autoimmunity and lethality. Antisera from these mice recognized multiple self-cellular proteins. These data provide strong evidence that negative selection is crucial for establishing T cell tolerance. Current projects are aimed to understand the mechanisms and requirements of these various apoptotic pathways in central tolerance to prevent autoimmunity.
Members of the Tumor Necrosis Factor (TNF) superfamily are involved in diverse biological function, including inflammation, prevention of autoimmunity, cancer, and many others. Indeed, members of this family have become successful targets of drug development for many human diseases. We are interested in the signal transduction events of a subset of the TNF superfamily that can initiate cell death. We have shown that FADD is a universal adapter for all TNF receptor-mediated death. Surprisingly, FADD and caspase-8 are also negative regulators of an alternative form of cell death called necroptosis (programmed necrosis). Loss of FADD leads to resistance to apoptosis but FADD-deficient cells undergo necroptosis instead. Current projects are aimed to understand the physiological role of this "hidden" cell death pathway in infectious diseases and cancer.
Deletion of FADD in Macrophages and Granulocytes Results in RIP3- and MyD88-dependent Systemic Inflammation [Schock+, S. N., Young+, J. A., He, T. H., Sun, Y. and Winoto, A. (2015) PLoS One, 10:e0124391. +co-authorship]
T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity [Burger, M.L., Leung, K.K., Bennett, M.J., and Winoto, A. (2014) eLife 3:e03468. doi: http://dx.doi.org/10.7554/eLife.03468]
Premalignant PTEN-deficient thymocytes activate microRNAs miR-146a and miR-146b as a cellular defense against malignant transformation [Burger+, M. L., Xue+, L., Sun, Y., Kang, C. and Winoto, A. (2014) Blood, 123, 4089-4100. +co-authorship]
Commensal Microbiota are Required for Systemic Inflammation Triggered by Necrotic Dendritic Cells [Young, J. A., He, T.H., Reizis, B. and Winoto, A. (2013) Cell Reports, 3, 1932-1944]
Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production [Young*, J. A., Sermwittayawong*, D., Kim, H., Nandu, S., An, N.S., Erdjument-Bromage, H., Tempst, P., Coscoy, L. and Winoto, A. (2011) J. Biol. Chem. 286, 6521-6531. *co-authorship]
FADD is a negative regulator of T cell receptor-mediated necroptosis [Osborn, S. L., Diehl, G., Hans, S-J., Xue, L., Kurd, N., Hsieh, K, Cado, D., Robey, E.A. and Winoto, A. (2010) Proc. Natl. Acad. Sci. USA. e107, 13034-13039]
Protein Kinase C regulates mitochondrial targeting of Nur77 and its family member Nor-1 in thymocytes undergoing apoptosis [Thompson, J., Burger, M., Whang, H. and Winoto, A. (2010) Eur. J. Immunol. 40, 2041-2049]
Last Updated 2015-05-29