Timothy E Osullivan

Associate Professor, MIMG, University of California Los Angeles

The O'Sullivan lab takes a collaborative interdisciplinary cyclical translation approach to discover new therapeutics that harness the power of the immune system. Starting with clinical datasets, we model cell-cell interactions and critical gene regulatory networks to understand the main mechanisms that drive disease during cancer, obesity, viral infection, and tissue injury. We then model these mechanisms using clinically relevant mouse models to discover conserved pathways that can be either drugged or engineered to enhance immune function. We focus on 3 fundamental research questions that have resulted in groundbreaking discoveries: 1. What are the critical gene regulatory networks in human innate immunity? Although decades of research using mouse models have contributed to our understanding of the innate immune system, many findings in mice do not translate to humans. Furthermore, transcriptomics experiments in human innate immune cells suggest that the pathways induced in response to pro-inflammatory signals can be distinct from those in mice. These findings suggest that there is a pressing need to understand the molecular mechanisms that regulate human innate immunity. Our research program is designed to address this need through targeted CRISPR screens and bioinformatic analyses of patient samples. 2. What are the mechanisms that regulate the lifespan of innate immune cells? Natural Killer (NK) cells are unique in that they share attributes of both the innate and adaptive immune system. NK cells can undergo clonal proliferation, contraction, and memory formation in response to viral infections such as cytomegalovirus (CMV). We are fascinated with understanding how a normally short-lived cell (~7 days) can dramatically enhance its lifespan to over a year following viral infection. Another arm of our research program is dedicated to understanding the molecular mechanisms that regulate NK cell persistence. 3. How is inflammation initiated and maintained by the innate immune system? A complete immune response is enabled by the concerted activation of tissue-resident and circulating immune cells. However, we are only beginning to understand the role of tissue-resident immune cells in host physiology and disease. Our research interests have focused on the role of tissue-resident type 1 innate immune cells (cDC1, NK cells, ILC1) in host protection and pathology in response to pathogen-induced and sterile inflammation.

Interests

Innate Immunity, CRISPR engineering, Immunometabolism, Tumor Immunology, Primary Immunodeficiency, Natural Killer Cells, Systems Immunology, Dendritic Cells

Education and Training

Memorial Sloan Kettering Cancer Center6/2017Immunology
UCSDPhD9/2012Cancer Immunology
Cornell UniversityBS12/2008Biomedical Engineering

Awards and Honors

  • American Cancer Society Postdoctoral Fellowship, MSKCC, 2015-2017.
  • AAI 2016 Thermo Fisher Trainee Achievement Award, MSKCC, 2016.
  • UCSD-UCLA Diabetes Research Center Junior Faculty Award, UCLA, 2019.
  • Regeneron New Investigator Award for Excellence in Cytokine and Interferon Research, UCLA, 2022.
  • UCLA Life Sciences Excellence in Research Award, UCLA, 2021.

Publications

  1. Li JH, Zhou A, Lee CD, Shah SN, Ji JH, Senthilkumar V, Padilla ET, Ball AB, Feng Q, Bustillos CG, Riggan L, Greige A, Divakaruni AS, Annese F, Cooley-Coleman J, Skinner SA, Cowan CW, O'Sullivan TE. MEF2C regulates NK cell effector functions through control of lipid metabolism.. Nature immunology, 2024.
  2. Hermans L, O'Sullivan TE. No time to die: Epigenetic regulation of natural killer cell survival.. Immunological reviews, 2024.
  3. Li R, Galindo CC, Davidson D, Guo H, Zhong MC, Qian J, Li B, Ruzsics Z, Lau CM, O'Sullivan TE, Vidal SM, Sun JC, Veillette A. Suppression of adaptive NK cell expansion by macrophage-mediated phagocytosis inhibited by 2B4-CD48.. Cell reports, 2024.
  4. Hildreth AD, Padilla ET, Gupta M, Wong YY, Sun R, Legala AR, O'Sullivan TE. Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.. Nature metabolism, 2023.
  5. Li JH, Hepworth MR, O'Sullivan TE. Regulation of systemic metabolism by tissue-resident immune cell circuits.. Immunity, 2023.
  6. Cheng MI, Li JH, Riggan L, Chen B, Tafti RY, Chin S, Ma F, Pellegrini M, Hrncir H, Arnold AP, O'Sullivan TE, Su MA. The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences.. Nature immunology, 2023.
  7. Hildreth AD, Padilla ET, Tafti RY, Legala AR, O'Sullivan TE. Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production.. Cell reports, 2023.
  8. Schuster IS, Sng XYX, Lau CM, Powell DR, Weizman OE, Fleming P, Neate GEG, Voigt V, Sheppard S, Maraskovsky AI, Daly S, Koyama M, Hill GR, Turner SJ, O'Sullivan TE, Sun JC, Andoniou CE, Degli-Esposti MA. Infection induces tissue-resident memory NK cells that safeguard tissue health.. Immunity, 2023.
  9. Krämer B, Nalin AP, Ma F, Eickhoff S, Lutz P, Leonardelli S, Goeser F, Finnemann C, Hack G, Raabe J, ToVinh M, Ahmad S, Hoffmeister C, Kaiser KM, Manekeller S, Branchi V, Bald T, Hölzel M, Hüneburg R, Nischalke HD, Semaan A, Langhans B, Kaczmarek DJ, Benner B, Lordo MR, Kowalski J, Gerhardt A, Timm J, Toma M, Mohr R, Türler A, Charpentier A, van Bremen T, Feldmann G, Sattler A, Kotsch K, Abdallah AT, Strassburg CP, Spengler U, Carson WE, Mundy-Bosse BL, Pellegrini M, O'Sullivan TE, Freud AG, Nattermann J. Single-cell RNA sequencing identifies a population of human liver-type ILC1s.. Cell reports, 2023.
  10. Wang J, Chang CY, Yang X, Zhou F, Liu J, Zhu S, Yu XZ, Liu C, O'Sullivan TE, Xie P, Feng Z, Hu W. Leukemia inhibitory factor protects against graft-versus-host disease while preserving graft-versus-leukemia activity.. Blood, 2022.
  11. Riggan L, Ma F, Li JH, Fernandez E, Nathanson DA, Pellegrini M, O'Sullivan TE. The transcription factor Fli1 restricts the formation of memory precursor NK cells during viral infection.. Nature immunology, 2022.
  12. Li JH, O'Sullivan TE. Back to the Future: Spatiotemporal Determinants of NK Cell Antitumor Function.. Frontiers in immunology, 2022.
  13. Hildreth AD, Ma F, Wong YY, Sun R, Pellegrini M, O'Sullivan TE. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity.. Nature immunology, 2021.
  14. Riggan L, Shah S, O'Sullivan TE. Arrested development: suppression of NK cell function in the tumor microenvironment.. Clinical & translational immunology, 2021.
  15. Hildreth AD, Riggan L, O'Sullivan TE. CRISPR-Cas9 Ribonucleoprotein-Mediated Genomic Editing in Primary Innate Immune Cells.. STAR protocols, 2020.
  16. Riggan L, Hildreth AD, Rolot M, Wong YY, Satyadi W, Sun R, Huerta C, O'Sullivan TE. CRISPR-Cas9 Ribonucleoprotein-Mediated Genomic Editing in Mature Primary Innate Immune Cells.. Cell reports, 2020.
  17. Nabekura T, Riggan L, Hildreth AD, O'Sullivan TE, Shibuya A. Type 1 Innate Lymphoid Cells Protect Mice from Acute Liver Injury via Interferon-γ Secretion for Upregulating Bcl-xL Expression in Hepatocytes.. Immunity, 2019.
  18. O'Sullivan TE. Dazed and Confused: NK Cells.. Frontiers in immunology, 2019.
  19. Riggan L, Freud AG, O'Sullivan TE. True Detective: Unraveling Group 1 Innate Lymphocyte Heterogeneity.. Trends in immunology, 2019.
  20. Weizman OE, Song E, Adams NM, Hildreth AD, Riggan L, Krishna C, Aguilar OA, Leslie CS, Carlyle JR, Sun JC, O'Sullivan TE. Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12.. Nature immunology, 2019.
  21. Hildreth AD, O'Sullivan TE. Tissue-Resident Innate and Innate-Like Lymphocyte Responses to Viral Infection.. Viruses, 2019.
  22. O'Sullivan TE, Sun JC. Determination of the Fate and Function of Innate Lymphoid Cells Following Adoptive Transfer of Innate Lymphoid Cell Precursors.. Methods in molecular biology (Clifton, N.J.), 2018.
  23. Rapp M, Lau CM, Adams NM, Weizman OE, O'Sullivan TE, Geary CD, Sun JC. Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses.. Science immunology, 2017.
  24. Weizman OE, Adams NM, Schuster IS, Krishna C, Pritykin Y, Lau C, Degli-Esposti MA, Leslie CS, Sun JC, O'Sullivan TE. ILC1 Confer Early Host Protection at Initial Sites of Viral Infection.. Cell, 2017.
  25. O'Sullivan TE, Sun JC. Innate Lymphoid Cell Immunometabolism.. Journal of molecular biology, 2017.
  26. Adams NM, O'Sullivan TE, Geary CD, Karo JM, Amezquita RA, Joshi NS, Kaech SM, Sun JC. NK Cell Responses Redefine Immunological Memory.. Journal of immunology (Baltimore, Md. : 1950), 2016.
  27. Saddawi-Konefka R, Seelige R, Gross ET, Levy E, Searles SC, Washington A, Santosa EK, Liu B, O'Sullivan TE, Harismendy O, Bui JD. Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.. Cell reports, 2016.
  28. O'Sullivan TE, Rapp M, Fan X, Weizman OE, Bhardwaj P, Adams NM, Walzer T, Dannenberg AJ, Sun JC. Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance.. Immunity, 2016.
  29. O'Sullivan TE, Geary CD, Weizman OE, Geiger TL, Rapp M, Dorn GW, Overholtzer M, Sun JC. Atg5 Is Essential for the Development and Survival of Innate Lymphocytes.. Cell reports, 2016.
  30. O'Sullivan TE, Sun JC, Lanier LL. Natural Killer Cell Memory.. Immunity, 2015.
  31. O'Sullivan TE, Johnson LR, Kang HH, Sun JC. BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory.. Immunity, 2015.
  32. O'Sullivan TE, Sun JC. Generation of Natural Killer Cell Memory during Viral Infection.. Journal of innate immunity, 2015.
  33. Geiger TL, Abt MC, Gasteiger G, Firth MA, O'Connor MH, Geary CD, O'Sullivan TE, van den Brink MR, Pamer EG, Hanash AM, Sun JC. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens.. The Journal of experimental medicine, 2014.