RESEARCH SUMMARY

Current research in the laboratory addresses various issues related to the biology of NK cells and in particular the receptor NKG2D. Some of topics of investigation represent the continuation of projects ongoing in the lab, before the move from Cambridge in October 2008, while others are new projects begun in the CNB:

Traffic and function of the NKG2D receptor.

We have identified amino acids in the cytoplasmic tail of NKG2D and DAP10 that regulate internalisation of the receptor complex, and are now analysing how receptor recycling alters the threshold for signalling. We have described how NKG2D/DAP10 receptor complexes polarise to the cytotoxic immune synapse in secretory lysosomes/lytic granules.

We are now studying how the functional significance of the presence of this receptor complex in the lytic granules affects the fusion of the granules with the target cell membrane for delivery of the lethal hit.

We, and others, have described that chronic interactions with NKG2D-ligand-expressing target cells produces NK cell exhaustion/anergy. We are now analysing the molecular basis of this defect.

The use of human cytomegalovirus as a tool to study the regulation of expression of NKG2D ligands.

We have a longstanding interest in studying the interactions between viruses and cells of the immune system as a strategy to gain insight into functionally important features of the immune system. We noted that infection with human cytomegalovirus (HCMV) induces high levels of shedding of NKG2D ligands, and are characterising the biochemical basis of this effect in vitro.

We have also gone on to show that the NK cells and CD8+ T cells of patients with active CMV-related disease have markedly reduced levels of NKG2D receptor expression in vivo, and are now working to understand the mechanisms underlying this phenomenon.

These experiments are being done in collaboration with groups in the university teaching hospitals Gregorio Marañon and 12 de Octubre, and we are beginning to work with investigators in the Infectious Diseases Department, Hospital Clinic-HIV Development Program in Catalonia, Institut d'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Spain.