Immunoregulation This laboratory investigates how CD8+ T lymphocytes acquire and memorise the ability to kill infected cells and tumours so that these processes can be controlled through improved vaccine design or immunotherapy
CD8+ cytolytic T lymphocytes (CTL) control pathogen-infected cells and tumours by releasing cytotoxic molecules (perforin and granzymes A and B) and regulatory cytokines. Once the challenge has been overcome, these effector CTL give rise to memory cells that can be reactivated if the pathogen or tumour returns. This laboratory is examining the development of effector and memory CTL to learn how their activities can be controlled.
Laboratory Head: Professor Anne Kelso
Research Highlights Showed that CD8+ T cells activated in vivo in the presence of IL-4 can develop into poorly cytolytic, type 2-polarised CD8low cells with reduced ability to eliminate tumours.
The laboratory previously reported that exposure to the cytokine interleukin-4 (IL-4) in vitro drives CD8+ T cells to develop into an unusual CD8low effector cell which produces IL-4, is poorly cytolytic and shows reduced ability to eliminate tumours. During this year, for the first time, conditions in which these cells develop in vivo were identified. Transgenic ovalbumin (OVA)specific CD8low cells generated in vivo faithfully recapitulated the phenotype and function of those generated in vitro, including poor control of OVA-expressing tumour growth in vivo. These studies have provided novel insights into the regulation of expression of the CD8
Showed that resting memory CD8+ T cells are not irreversibly programmed during priming but instead have the potential to express new functions when exposed to new stimuli on reactivation.
CD8+ T cells activated in vivo in an IL-4-rich environment have reduced ability to control tumour growth
Tumour Weight (mg)
Na誰ve transgenic CD8+ T cells were activated in vivo with tumour cells that do or do not express IL-4. The T cells were then recovered, transferred into a new host and challenged with the IL-4-negative tumour. Tumours were measured ten days later.
IL-4+
IL-4-
Priming tumour type 22
co-receptor and key molecules responsible for cytolytic function. Whereas IL-4 inhibits the expression of perforin and granzyme B in CTL, the laboratory has found that it can markedly enhance granzyme A expression. This effect on granzyme A depends on cell-cell contact. Experiments with CD8+ T cells that lack the IL-4 receptor suggest that IL-4 induces a second signal which is then responsible for the elevation of granzyme A levels. Some years ago, the group established that individual na誰ve CD8+ T cells are multipotential, i.e. they can develop into effector cells with different functions depending on signals they received during activation. Effector cells, by contrast, exhibit much reduced flexibility. Work in the past year has shown that memory CD8+ T cell populations contain significant numbers of multipotential cells. Progress has been made in defining the surface phenotype of these flexible memory cells and the requirements for expression of their multipotentiality. Immunoregulation researchers from left: Back: Adriana Baz, Simon Apte. Front: Kathy Buttigieg and Penny Groves