Prof. Derek Doherty

Research Description:

Our research is aimed at finding out how the immune system protects against or causes disease in humans and how it can be manipulated for the development of novel therapies. We are particularly interested in populations of 'innate T cells' (natural killer T cells, gamma/delta T cells and mucosal-associated invariant T cells), which play early roles in the control of immune responses and tissue homeostasis. Innate T cells recognise non-peptide antigens presented by antigen-presenting molecules other than major histocompatibility complex molecules. They can be trained to prevent and treat infectious and immune-mediated diseases and cancers in animal models. Various innate T cell populations are being targeted in clinical trials for cancer in humans, and although the results are promising, no such cellular therapy has yet received approval. In order to improve the efficacy of current innate T cell therapies and to develop new treatments, we are investigating the molecular and cellular interactions that take place between innate T cells, pathogens and other cells. We have found that innate T cells are heterogeneous with diverse effector functions including tumour cell killing, cytokine release and contact-dependent stimulatory and regulatory interactions with monocytes, macrophages, dendritic cells and B cells. These activities can be selectively activated by treating them with antigens and cytokines. In collaboration with clinical colleagues, we have found that innate T cell populations are numerically and/or functionally impaired in patients with viral hepatitis B, HIV, candidiasis, oesophageal, stomach, colorectal, liver, lung and blood cancers, post-operative infection and sepsis, coeliac disease, autoimmune vasculitis, antibody deficiencies and neonatal encephalopathy. Furthermore, rapid reconstitution of some innate T cell populations after allogeneic stem cell transplantation is associated with favourable outcomes. We are currently attempting to manipulate innate T cells to promote the generation of desirable immune responses for the treatment of cancer and infectious disease.