Prof Phil Hodgkin, Lab Head | WEHI Researcher Profile

Q: A computational model of the immune system

The development of mathematical models of the T and B cell adaptive immune response has developed rapidly over the last several years and the probabilistic principles for codifying modules of cellular behavior have proved increasingly successful. All members of the lab work either with, or on improving such models directly. New resources are being developed as software for the immunology community. Experiments to inform the models and to test predictions are made from single cell tracking, from cell division and differentiation tracking and from fate mapping performed both in vitro and in vivo.

Q: The biology of T and B cells and the cellular calculus

There is still much to learn about the normal biology of both T and B lymphocytes in the immune response. We are particularly keen to understand how cells add signals together and adjust to changing levels and combinations of the many different cytokines and costimuli on offer during an immune challenge. To reveal this ‘cellular calculus’ we measure cell behavior, at single cell and population level to learn the rules of addition and to predict the net outcomes. The effects of drugs and genetic manipulations on modular components of the cell are also being measured with the aim to develop a principle for predictive immunotherapy and in silico drug screening.

Q: Variation in the human immune system and its importance to disease

Our principles of cellular calculus and single cell behavior have been developed using model systems. We are asking whether the same principles operate for people and the quantitative methods we have developed could help stratify and screen for genetic deficiencies and susceptibilities. Importantly we aim to identify how multiple small quantitative changes in cellular circuits can add up to powerful immune disorders such as autoimmunity. Our first target is to examine Common Variable Immunodeficiency and move from there to more complex immune disorders.

About

Our lab has a long-standing interest in understanding how the immune system operates. By combining experiment and theory we aim to identify and codify how logical cellular operations can be altered and controlled by a range of signals. The results lead to powerful, predictive quantitative models that improve our understanding and provide new tools to dissect the system further. Our target is the immune system, but our developing and improving theories apply equally to blood cell development and cancer biology.

Our immune system is critical for health, but its complex operation makes it difficult to understand and control. This hurdle is important as immune dysfunction is a major contributor to human diseases, accounting for a significant health burden. In the Hodgkin lab we aim to understand how the cells of the immune system make decisions that underlie immune health or head down the path of disease causing ‘errors’ that lead to conditions such as autoimmunity or allergies. By combining experiment and theory we identify how cellular functions are altered and controlled by a range of cell communication signals, alone and in combination. The results help formulate predictive, quantitative models that operate at cell and molecular level to improve our understanding of immunity and provide new tools to dissect the immune system further.

Our results to date support a revision of the foundational theory for the adaptive immune response that incorporates ideas from many fields, including statistical physics. This is because we discovered cells use randomising processes to allocate, cells to different tasks. We test and inform the developing framework by experiments such as video microscopy and time series division tracking to watch T and B cells in the act of making decisions and modifying their behaviour.

Our resulting mathematical models and quantitative methods allow us to measure differences between individuals and provide insights into the complex causes of underlying immune dysfunction.

Building and testing this theory forms one of the major goals of the Snow Centre for Immune Health. Within the Centre we are revising and updating clonal selection theory to develop methods to assess the health of immune cells sampled from individuals. Results can be used to build personalised models of immune decision-making and help identify complex causes of immune errors as well as provide insights into selecting appropriate treatments.

Education

Publications

Selected publications from Prof Phil Hodgkin

Biemond M, Vremec D, Gray DH, Hodgkin PD, Heinzel S. Programmed death receptor 1 (PD‐1) ligand Fc fusion proteins reduce T‐cell proliferation in vitro independently of PD‐1. Immunology and Cell Biology. 2024;102(2):10.1111/imcb.12714

Heinzel S, Cheon H, Belz GT, Hodgkin PD. Survival and division fate programs are preserved but retuned during the naïve to memory CD8+ T‐cell transition. Immunology and Cell Biology. 2024;102(1):10.1111/imcb.12699

Farchione AJ, Cheon H, Hodgkin PD, Bryant VL. Quantifying Human Naïve B Cell Proliferation Kinetics and Differentiation in Controlled In Vitro Cell Culture. Methods in Molecular Biology. 2024;2826:10.1007/978-1-0716-3950-4_13

Hodgkin PD. Kevin Lafferty and the lymphocyte costimulator: theory and practice in Canberra. Immunology and Cell Biology. 2023;101(8):10.1111/imcb.12683

Robinson MJ, Ding Z, Dowling MR, Hill DL, Webster RH, McKenzie C, Pitt C, O’Donnell K, Mulder J, Brodie E, Hodgkin PD, Wong NC, Quast I, Tarlinton DM. Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan. Immunity. 2023;56(7):10.1016/j.immuni.2023.04.015

Kong IY, Trezise S, Light A, Todorovski I, Arnau GM, Gadipally S, Yoannidis D, Simpson KJ, Dong X, Whitehead L, Tempany JC, Farchione AJ, Sheikh AA, Groom JR, Rogers KL, Herold MJ, Bryant VL, Ritchie ME, Willis SN, Johnstone RW, Hodgkin PD, Nutt SL, Vervoort SJ, Hawkins ED. Epigenetic modulators of B cell fate identified through coupled phenotype-transcriptome analysis. Cell Death & Differentiation. 2022;29(12):10.1038/s41418-022-01037-5

Robinson MJ, Dowling MR, Pitt C, O’Donnell K, Webster RH, Hill DL, Ding Z, Dvorscek AR, Brodie EJ, Hodgkin PD, Quast I, Tarlinton DM. Long-lived plasma cells accumulate in the bone marrow at a constant rate from early in an immune response. Science Immunology. 2022;7(76):10.1126/sciimmunol.abm8389

Horton MB, Cheon H, Duffy KR, Brown D, Naik SH, Alvarado C, Groom JR, Heinzel S, Hodgkin PD. Lineage tracing reveals B cell antibody class switching is stochastic, cell-autonomous, and tuneable. Immunity. 2022;55(10):10.1016/j.immuni.2022.08.004

Zotos D, Quast I, Li-Wai-Suen CSN, McKenzie CI, Robinson MJ, Kan A, Smyth GK, Hodgkin PD, Tarlinton DM. The concerted change in the distribution of cell cycle phases and zone composition in germinal centers is regulated by IL-21. Nature Communications. 2021;12(1):10.1038/s41467-021-27477-0

Naik S, Tian L, Tomei S, Schreuder J, Weber T, Amman-Zalcenstein D, Lin D, Tran J, Audiger C, Bahlo M, Chu M, Diakumis P, Gouil Q, Hilton A, Jarratt A, Willson T, Kats L, kelly M, Pang ES, O’Keeffe M, Patton T, Sargeant T, Su S, Hodgkin P, Ng A, Ritchie M. 3104 – CLONAL MULTI-OMICS METHODS SIS-SEQ AND SIS-SKEW REVEAL BCOR AS A NEGATIVE REGULATOR OF EMERGENCY DENDRITIC CELL DEVELOPMENT. Experimental Hematology. 2021;100:10.1016/j.exphem.2021.12.321