Tim O’Sullivan, PH.D.
Our research is dedicated to understanding the molecular mechanisms responsible for protective or pathologic immune responses during cancer, viral infection, and obesity. We will exploit this knowledge to design effective therapeutic strategies with potential clinical applications for type II diabetes and cancer. Our research program is composed of three major directions:
- Mechanisms of immune surveillance and immune escape in cancer
Our research goal is to dissect the cellular and molecular mechanisms that control immune surveillance and tumor escape from immune surveillance. In particular, we are interested in studying the role of tissue-resident (dendritic cells, innate lymphoid cells (ILCs)) vs circulating innate immune cells (Natural Killer (NK) cells) in primary and metastatic melanoma and breast cancer. Furthermore, we are interested in the tumor cell-intrinsic mechanisms by which tumors escape NK cell mediated immune surveillance through suppression of interferon (IFN)-gamma inducible genes.
- Mechanisms of adipose tissue inflammation and insulin resistance during diet-induced obesity
Our research was the first to identify a novel subset of adipose-resident type 1 innate lymphoid cells (ILC1) that contribute to early adipose tissue inflammation during diet-induced obesity. We found that short-term high fat diet feeding lead to sustained IL-12 production in the adipose tissue, inducing high levels of IFN-gamma by ILC1 to contribute to proinflammatory macrophage accumulation and insulin resistance. Our current projects will identify the cellular sources of IL-12 in the adipose tissue, as well as test whether microbiome-dependent or independent signals contribute to IL-12 production. We also aim to fully characterize the immune composition of human adipose and liver samples through single cell sequencing and mass cytometry (CyTOF) experiments to examine clinical correlates in obese and type II diabetes patients.
- ILC responses to viral infection and generation of immunological memory
The innate immune system was previously considered to be composed of short-lived cells that perform effector functions during infection and then rapidly die once their task is accomplished. However, our studies and others suggest that ILCs posses characteristics of the adaptive immune system, such as clonal expansion, longevity, and immunological memory. We have recently demonstrated that virus-specific NK cells persist to form memory cells by removing damaged mitochondria through a process known as mitophagy. Current projects are aimed at understanding the molecular mechanisms that control the induction of autophagy and mitophagy in lymphocytes during viral infection, and to further understand the cell fate decisions that dictate memory cell formation and survival.
Dr. O’Sullivan is an Assistant Professor of Microbiology, Immunology, and Molecular Genetics. He received his Bachelors of Science Degree (B.S.) from Cornell University and his Doctor of Philosophy Degree (Ph.D.) in Biomedical Science from the University of California San Diego. Dr. O’Sullivan’s thesis work focused on the interactions between the innate immune system and cancer. Dr. O’Sullivan subsequently completed his American Cancer Society postdoctoral fellowship at Memorial Sloan Kettering Cancer Center where he studied the role of circulating and tissue-resident innate lymphoid cells (ILC) during viral infection and diet-induced obesity. Dr. O’Sullivan established his own laboratory at UCLA in 2017.
Weizman Orr-El, Adams Nicholas M, Schuster Iona, Krishna Chirag, Pritykin Yuri, Lau Colleen, Degli-Esposti Mariapia A, Leslie Christina S, Sun Joseph C, O’Sullivan Timothy E ILC1 Confer Early Host Protection at Initial Sites of Viral Infection. Cell. 2017; .
O’Sullivan Timothy E, Sun Joseph C Innate Lymphoid Cell Immunometabolism. Journal of molecular biology. 2017; .
O’Sullivan Timothy E, Rapp Moritz, Fan Xiying, Weizman Orr-El, Bhardwaj Priya, Adams Nicholas M, Walzer Thierry, Dannenberg Andrew J, Sun Joseph C Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance. Immunity. 2016; 45(2): 428-41.
Saddawi-Konefka Robert, Seelige Ruth, Gross Emilie T E, Levy Eric, Searles Stephen C, Washington Allen, Santosa Endi K, Liu Beichen, O’Sullivan Timothy E, Harismendy Olivier, Bui Jack D Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance. Cell reports. 2016; 16(9): 2348-58.
O’Sullivan Timothy E, Geary Clair D, Weizman Orr-El, Geiger Theresa L, Rapp Moritz, Dorn Gerald W, Overholtzer Michael, Sun Joseph C Atg5 Is Essential for the Development and Survival of Innate Lymphocytes. Cell reports. 2016; 15(9): 1910-9.
O’Sullivan Timothy E, Sun Joseph C, Lanier Lewis L Natural Killer Cell Memory. Immunity. 2015; 43(4): 634-45.
O’Sullivan Timothy E, Johnson Lexus R, Kang Helen H, Sun Joseph C BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory. Immunity. 2015; 43(2): 331-42.
O’Sullivan Timothy E, Sun Joseph C Generation of Natural Killer Cell Memory during Viral Infection. Journal of innate immunity. 2015; 7(6): 557-62.
Geiger Theresa L, Abt Michael C, Gasteiger Georg, Firth Matthew A, O’Connor Margaret H, Geary Clair D, O’Sullivan Timothy E, van den Brink Marcel R, Pamer Eric G, Hanash Alan M, Sun Joseph C Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. The Journal of experimental medicine. 2014; 211(9): 1723-31.
O’Sullivan Timothy, Saddawi-Konefka Robert, Gross Emilie, Tran Miller, Mayfield Stephen P, Ikeda Hiroaki, Bui Jack D Interleukin-17D mediates tumor rejection through recruitment of natural killer cells. Cell reports. 2014; 7(4): 989-98.
O’Sullivan Timothy, Saddawi-Konefka Robert, Vermi William, Koebel Catherine M, Arthur Cora, White J Michael, Uppaluri Ravi, Andrews Daniel M, Ngiow Shin Foong, Teng Michele W L, Smyth Mark J, Schreiber Robert D, Bui Jack D Cancer immunoediting by the innate immune system in the absence of adaptive immunity. The Journal of experimental medicine. 2012; 209(10): 1869-82.
O’Sullivan Timothy, Dunn Gavin P, Lacoursiere Daphne Y, Schreiber Robert D, Bui Jack D Cancer immunoediting of the NK group 2D ligand H60a. Journal of immunology (Baltimore, Md. : 1950). 2011; 187(7): 3538-45.