human immunology, organoids, infectious diseases, vaccine development, immune microenvironments, adaptive immunity
Although there is intense interest in improving vaccine design and efficacy, these efforts are hampered by a lack of knowledge about how human immune responses are coordinated and developed inside lymphoid tissues. The vaccine development process is traditionally empirical, expensive, labor-intensive, and slow, making it difficult to rapidly respond to pandemics and pathogens of global concern. Though blood-based assays are becoming increasingly sophisticated, these methods often fail to identify strong correlates of protection for many of the deadliest pathogens of our time as many important cell types that are responsible for developing adaptive immunity are not found in peripheral blood. One way to circumvent this problem is to use organoid technologies that recapitulate the major features of adaptive immunity in vitro for infection and vaccine testing.
Immune organoids can be produced from human tonsil tissues, spleen, and lymph nodes. These organoids respond appropriately to influenza vaccines and viruses and recapitulate many of the key features of the adaptive response, such as differentiation of B cells into plasmablasts, T cell activation, and specific antibody secretion. The major goals of the Wagar lab are to 1) expand this vaccine work to other infectious diseases such as SARS-CoV2, 2) unravel mechanisms involved in regulating human adaptive immunity, and 3) explain inter-individual variability in vaccine responsiveness. It is our hope that engineering strategies to help us dissect the mechanistic aspects of human immunity will accelerate and inform vaccine design.
Recipient of a 2022 Michelson Philanthropies and Science prize for Immunology
Lisa Wagar is an Assistant Professor in the Department of Physiology and Biophysics at the University of California, Irvine where her lab studies human vaccine responses and develops tools to investigate human adaptive immunity. Lisa is passionate about translational human immunology and collaborative efforts to improve and accelerate vaccine design for infectious diseases of global concern. UC Irvine is uniquely situated for multidisciplinary and collaborative efforts in vaccine immunology, with abundant interactions between the Department of Physiology and Biophysics, Institute for Immunology, and the Vaccine R&D Center. The mission of the Wagar lab is to accelerate vaccine design and immunotherapies to ultimately understand, treat, and prevent human disease.
Dr. Wagar received her PhD in Immunology (2013) at the University of Toronto under the mentorship of Dr. Tania Watts. During her doctoral work, Lisa completed projects related to human T cell responses against influenza and proposed vaccination strategies to promote long-term protection against influenza disease. She then went on to a postdoctoral fellowship in Dr. Mark Davis’s lab at Stanford University, where she developed immune organoid technologies for studying human adaptive immune responses to influenza vaccination and infection in vitro.
Wagar LE, Salahudeen A, Constantz CM, Wendel BS, Lyons MM, Mallajosyula V, Jatt LP, Adamska JZ, Blum LK, Gupta N, Jackson KJL, Yang F, Roltgen K, Roskin KM, Blaine KM, Meister KD, Ahmad IN, Cortese M, Dora EG, Tucker SN, Sperling AI, Jain A, Davies DH, Felgner PL, Hammer GB, Kim PS, Robinson WH, Boyd SD, Kuo CJ, Davis MM. Modeling human adaptive immune responses with tonsil organoids. Nat Med. 2021 Jan;27(1):125-135. doi: 10.1038/s41591-020-01145-0. Epub 2021 Jan 11. PubMed PMID: 33432170.
Salahudeen AA, Choi SS, Rustagi A, Zhu J, van Unen V, de la O SM, Flynn RA, Margalef-Catala M, Santos AJM, Ju J, Batish A, Usui T, Zheng GXY, Edwards CE, Wagar LE, Luca V, Anchang B, Nagendran M, Mguyen K, Hart DJ, Terry JM, Belgrader P, Ziraldo SB, Mikkelsen TS, Harbury PB, Glenn JS, Garcia KC, Davis MM, Baric RS, Sabatti C, Amieva MR, Blish CA, Desai TJ, Kuo CJ. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. Nature. 2020 Dec;588(7839):670-675. doi: 10.1038/s41586-020-3014-1. Epub 2020 Nov 25. Pubmed PMID: 33238290.
Glass DR, Tsai AG, Oliveria JP, Hartmann FJ, Kimmey SC, Calderon AA, Borges L, Glass MC, Wagar LE, Davis MM, Bendall SC. An Integrated Multi-omic Single-Cell Atlas of Human B Cell Identity. Immunity. 2020 Jul 14;53(1):217-232.e5. doi: 10.1016/j.immuni.2020.06.013. PubMed PMID: 32668225; PubMed Central PMCID: PMC7369630.
Chen B, Khodadoust MS, Olsson N, Wagar LE, Fast E, Liu CL, Muftuoglu Y, Sworder BJ, Diehn M, Levy R, Davis MM, Elias JE, Altman RB, Alizadeh AA. Predicting HLA class II antigen presentation through integrated deep learning. Nat Biotechnol. 2019 Nov;37(11):1332-1343. doi: 10.1038/s41587-019-0280-2. Epub 2019 Oct 14. PubMed PMID: 31611695; PubMed Central PMCID: PMC7075463.
Wagar LE, Bolen CR, Sigal N, Lopez Angel CJ, Guan L, Kirkpatrick BD, Haque R, Tibshirani RJ, Parsonnet J, Petri WA Jr, Davis MM. Increased T Cell Differentiation and Cytolytic Function in Bangladeshi Compared to American Children. Front Immunol. 2019;10:2239. doi: 10.3389/fimmu.2019.02239. eCollection 2019. PubMed PMID: 31620139; PubMed Central PMCID: PMC6763580.
Nielsen SCA, Roskin KM, Jackson KJL, Joshi SA, Nejad P, Lee JY, Wagar LE, Pham TD, Hoh RA, Nguyen KD, Tsunemoto HY, Patel SB, Tibshirani R, Ley C, Davis MM, Parsonnet J, Boyd SD. Shaping of infant B cell receptor repertoires by environmental factors and infectious disease. Sci Transl Med. 2019 Feb 27;11(481). doi: 10.1126/scitranslmed.aat2004. PubMed PMID: 30814336; PubMed Central PMCID: PMC6733608.
Wagar LE. Live Cell Barcoding for Efficient Analysis of Small Samples by Mass Cytometry. Methods Mol Biol. 2019;1989:125-135. doi: 10.1007/978-1-4939-9454-0_9. PubMed PMID: 31077103.
Wagar LE, DiFazio RM, Davis MM. Advanced model systems and tools for basic and translational human immunology. Genome Med. 2018 Sep 28;10(1):73. doi: 10.1186/s13073-018-0584-8. Review. PubMed PMID: 30266097; PubMed Central PMCID: PMC6162943.
Alcántara-Hernández M, Leylek R, Wagar LE, Engleman EG, Keler T, Marinkovich MP, Davis MM, Nolan GP, Idoyaga J. High-Dimensional Phenotypic Mapping of Human Dendritic Cells Reveals Interindividual Variation and Tissue Specialization. Immunity. 2017 Dec 19;47(6):1037-1050.e6. doi: 10.1016/j.immuni.2017.11.001. Epub 2017 Dec 5. PubMed PMID: 29221729; PubMed Central PMCID: PMC5738280.
Zhou AC, Wagar LE, Wortzman ME, Watts TH. Intrinsic 4-1BB signals are indispensable for the establishment of an influenza-specific tissue-resident memory CD8 T-cell population in the lung. Mucosal Immunol. 2017 Sep;10(5):1294-1309. doi: 10.1038/mi.2016.124. Epub 2017 Jan 4. PubMed PMID: 28051085.
Glanville J, Huang H, Nau A, Hatton O, Wagar LE, Rubelt F, Ji X, Han A, Krams SM, Pettus C, Haas N, Arlehamn CSL, Sette A, Boyd SD, Scriba TJ, Martinez OM, Davis MM. Identifying specificity groups in the T cell receptor repertoire. Nature. 2017 Jul 6;547(7661):94-98. doi: 10.1038/nature22976. Epub 2017 Jun 21. PubMed PMID: 28636589; PubMed Central PMCID: PMC5794212.
Khodadoust MS, Olsson N, Wagar LE, Haabeth OA, Chen B, Swaminathan K, Rawson K, Liu CL, Steiner D, Lund P, Rao S, Zhang L, Marceau C, Stehr H, Newman AM, Czerwinski DK, Carlton VE, Moorhead M, Faham M, Kohrt HE, Carette J, Green MR, Davis MM, Levy R, Elias JE, Alizadeh AA. Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens. Nature. 2017 Mar 30;543(7647):723-727. doi: 10.1038/nature21433. Epub 2017 Mar 22. PubMed PMID: 28329770; PubMed Central PMCID: PMC5808925.
Qi Q, Cavanagh MM, Le Saux S, Wagar LE, Mackey S, Hu J, Maecker H, Swan GE, Davis MM, Dekker CL, Tian L, Weyand CM, Goronzy JJ. Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals. PLoS Pathog. 2016 Oct;12(10):e1005892. doi: 10.1371/journal.ppat.1005892. eCollection 2016 Oct. PubMed PMID: 27764254; PubMed Central PMCID: PMC5072604.
Wagar LE, Rosella L, Crowcroft N, Lowcock B, Drohomyrecky PC, Foisy J, Gubbay J, Rebbapragada A, Winter AL, Achonu C, Ward BJ, Watts TH. Humoral and cell-mediated immunity to pandemic H1N1 influenza in a Canadian cohort one year post-pandemic: implications for vaccination. PLoS One. 2011;6(11):e28063. doi: 10.1371/journal.pone.0028063. Epub 2011 Nov 23. PubMed PMID: 22132212; PubMed Central PMCID: PMC3223223.
Wagar LE, Gentleman B, Pircher H, McElhaney JE, Watts TH. Influenza-specific T cells from older people are enriched in the late effector subset and their presence inversely correlates with vaccine response. PLoS One. 2011;6(8):e23698. doi: 10.1371/journal.pone.0023698. Epub 2011 Aug 22. PubMed PMID: 21887299; PubMed Central PMCID: PMC3161762.
Bill & Melinda Gates Foundation. "Sex-based Responses to Vaccines and Adjuvants in Tonsil Organoid System"
Wellcome Leap HOPE initiative. "Predicting immunogenicity using human tonsil organoids"
UCI CFCCC. "Human lymphoma organoids as a screening platform for drug discovery and precision medicine in non-Hodgkin lymphoma"
Wellcome Leap HOPE initiative focused study. "The Ten Million T cells study"
Vaccine R&D Center
Institute for Immunology
Center for Virus Research
Chao Family Comprehensive Cancer Center