Work in the Division of Immunology covers three mains areas:
Immunology is a key discipline in the Department of Medicine and PIs are discussed in specific subject areas and here:
The Griffiths lab (based in CIMR) studies cytotoxic T lymphocytes (CTL) and Natural Killer (NK) cells, which use polarized secretion to destroy virally infected and tumorigenic target cells. Specialised secretory lysosomes, containing the pore forming protein perforin and a series of serine proteases, termed granzymes deliver the lethal hit in a specialized domain of the immunological synapse. The research is focused on understanding the molecular basis of polarized secretion from CTLs and has used a series of rare genetic diseases including Hermansky-Pudlak and Haemophagocytic syndromes to identify the roles of proteins involved in secretion from CTL and NK cells.
The James lab (based in the university unit of the MRC-LMB) focuses on how T cells discriminate between healthy and infected cells to initiate an appropriate immune response. The T-cell signalling network is complex, making it difficult to understand how these cells function at the level of the individual molecules involved. The James lab have created a ‘model’ T cell, capable of replicating the early decision-making process. The lab uses confocal microscopy with chemical or light-mediated control of cell signalling to probe the molecular details of T-cell activation. They have shown how T‑cell receptor engagement initiates downstream signalling and has allowed new hypotheses of ligand discrimination to be tested back in T cells.
The Lehner lab (based in CIMR) uses genetic (human haploid genetic screens) together with functional proteomic approaches to study the mechanisms by which viruses evade immune recognition. They recently developed ‘plasma membrane profiling’ an unbiased proteomic approach to analyze how viruses alter expression of any cell surface receptor to enable their replication. This powerful approach has identified novel immune as well as metabolic receptors, such as ABC transporters downregulated by latent human cytomegalovirus infection and is now being used to interrogate cell surface receptor regulation by different intracellular pathogens.
The Ramakrishnan lab (based in the university unit of the MRC-LMB) studies tuberculosis using the zebrafish as a model host. The optical transparency and genetic tractability of the zebrafish have allowed for real-time viewing of the steps of disease pathogenesis, their molecular and cellular mechanisms and their consequences. The ability to directly visualize the disease process has in turn led to surprising discoveries that have direct implications for both shorter and more effective treatment of human tuberculosis, and clinical trials and observational studies based on these findings are now in progress.
The Randow lab (based in the MRC-LMB) studies cell autonomous immunity. Our view of vertebrate host defense is shaped by the notion of a specialized set of immune cells as sole guardians of antimicrobial resistance, a concept that greatly underestimates the capacity of most cell lineages to defend themselves against infection. The aim of the Randow lab is to understand the principles and mechanisms for pathogen detection and destruction. Current emphasis is on the role of galectins as danger receptors, the ubiquitin-coating of cytosol-invading bacteria, and the role of autophagy cargo receptors in defending the cytosol against infection.
JR James & RD Vale Biophysical mechanism of T cell receptor triggering in a reconstituted system Nature (2012) 487:64-9.
C.J. Cambier, K.K. Takaki, R.P. Larson, R.E. Hernandez, D.M. Tobin, K.B. Urdahl, C.L. Cosma, L. Ramakrishnan. 2014. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505, 218-22
Randow F., MacMicking J.D., and James L.C. (2013). Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 340, 701–706.
de la Roche M, Ritter AT, Angus KL, Dinsmore C, Earnshaw CH, Reiter JF, Griffiths GM. Hedgehog signaling controls T cell killing at the immunological synapse Science. 2013 342(6163):1247-50.
WeekesMP, TanSYL, PooleE, TalbotS, AntrobusR, SmithDL, MontagC, GygiSP, SinclairJH, and LehnerPJ. Latency-associated degradation of the MRP1 drug transporter offers a therapeutic target for latent human cytomegalovirus (HCMV) infection. Science 2013 340(6129):199-202.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010; 330:827-830.
Bannard O, Kraman M, Fearon DT. Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science 2009; 323:505-509.
Jenkins MR, Tsun A, Stinchcombe JC, Griffiths GM. The strength of T cell receptor signal controls the polarization of cytotoxic machinery to the immunological synapse. Immunity 2009; 31:621-631.
Stagg HR, Thomas M, Van den Boomen D, Wiertz EH, Drabkin HA, Gemmill RM, Lehner PJ. The TRC8 E3 Ligase ubiquitinates MHC class I molecules before dislocation from the ER. J Cell Biol 2009; 186:685-92.
Viral avoidance and exploitation of the ubiquitin system. Randow F, Lehner PJ. Nature Cell Biol 2009; 11:527-34.