Dendritic cell Immunotherapy
Group Leader: Dr Clare Bennett
Dendritic cells (DC) are white blood cells that orchestrate immune responses. The manipulation of DC function is therefore an important target for the development of novel immuotherapeutics. The skin contains multiple phenotypically and spatially distinct DC populations, in particular Langerhans cells (LC) in the epidermis and dermal DC populations in the dermis. Our group is focused on understanding the functional relevance in vivo of the presence of these distinct DC populations for the development and control of skin immune responses. To this end we have a number of models in which different skin DC can be inducibly ablated in vivo.
We share LLR specialist funding with Ronjon Chakraverty (Transplant Immunology group) and have PhD students and post-docs on collaborative projects.
Dendritic cells and GVHD
DC have the potential to activate immune responses against tumours. However, in other settings DC may also drive unwanted immune responses resulting in immunopathology and tissue damage. This dichotomy is particularly relevant after bone marrow transplant when DC likely drive the anti-tumour response, but also activate donor T cells to destroy tissues such as the skin and intestine (graft-versus-host disease, GVHD). We are interested in understanding how skin DC drive cutaneous immunopathology, and in turn, how damage to the skin alters the resident DC network.
We have demonstrated that conventional recipient DC populations are required to activated donor T cells, but that LC are required to ‘license’ in-coming donor T cells to cause epithelial cell damage. Thus different DC populations interact with donor T cells at temporally and spatially distinct phases of the T cell response. Current projects in the lab include further investigation of the molecular and cellular mechanisms by which LC license effector T cell function, and investigation of the role of other DC populations in driving GVHD.
GVHD results in the killing of host immune cells in the skin, in particular LC, and the disruption of the epidermal layer. We are also interested in understanding how immune homeostasis is re-established in the skin after GVHD, and the effect this has on cutaneous immunity.
Targeting skin DC for leukaemia immunotherapy
The high numbers of accessible DC in the skin compared to other vaccination sites has made the skin an attractive target for vaccination protocols, and cutaneous vaccination has been shown to elicit potent systemic cellular immune responses in pre-clinical immunisation models. However, it is not known which skin DC are required to prime functional protective T cells following cutaneous immunisation. One of the aims of our lab is to use cutaneous vaccination with lentiviral vectors to investigate the requirement for different DC in the generation of post-vaccination immunity. The goal of our work is to address the feasibility of targeting skin DC via cutaneous lentiviral vaccination to prime functional anti-tumour T cell responses in vivo. This research, with that of our collaborators, will lead to the design of superior vaccination strategies for cancer immunotherapy.
Thomas Conlan (MRC Bench to Bedside PhD student)
Alastair Hotblack (MRC Bench to Bedside PhD student)
Cara Lomas (LLR post-doctoral fellow)
Dr Ronjon Chakraverty UCL
Dr Jessica Strid Imperial
Dr Carrie Ambler Durham University
Dr David Escors Pamplona, Spain
Dr Maria Rescigno Milan, Italy
Prof Fiona Powrie Oxford
Figure 1. Image showing the network of LC in the epidermis of the skin, and depletion of LC in our inducible ablation model.
Defining the role of DC in GVHD (with Dr Ronjon Chakraverty)
Donor T cells that have been infused as part of blood or bone marrow transplants become activated in response to recipient allo-antigens. This response may result in the destruction of recipient tumours (graft-versus-tumour) but can also lead to immunopathology due to the recognition of allo-antigens at sites such as the skin or the gut (graft-versus-host disease). In order to understand the mechanisms driving GVHD, and therefore to be able to separate beneficial graft-versus-tumour responses from GVHD, we have exploited our depletion models to specifically address the role of DC in GVHD. We have demonstrated that conventional recipient DC populations are required to activated donor T cells, but that LC are required to ‘license’ in-coming donor T cells to cause epithelial cell damage. Thus different DC populations interact with donor T cells at temporally and spatially distinct phases of the T cell response.
Figure 2. Photomicrographs showing the development of immunopathology (GVHD) in inflamed LC-competent but not LC-depleted skin.
Current projects in the lab include further investigation of the molecular and cellular mechanisms by which LC license effector T cell function, and investigation of the role of other DC populations in driving GVHD.
Annelise Soulier, Sandra M. Blois, Shivajanani Sivakumaran, Farnaz Fallah-Arani, Stephen Henderson, Barry Flutter, Elizabeth H. Rabbitt, Paul M. Stewart, Gareth G. Lavery, Clare Bennett, S. John Curnow and Ronjon Chakraverty. (2013) Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid. Blood. 122: 3288-97. Pubmed
Clare L. Bennett and Ronjon Chakraverty. (2011) Dendritic cells in tissues: in situ stimulation of immunity and immunopathology. Trends in Immunology. DOI 10.1016/j.it.2011.09.008. (Pubmed)
Katarzyna Karwacz, Christopher Bricogne, Frederick Arce, Clare Bennett, Mary Collins and David Escors. (2011) Programmed death ligand-1 co-stimulation provides the signal leading to ligand-induced T cell receptor down-modulation. EMBO Mol Med. 3: 581-92. (Pubmed)
Clare L. Bennett*, Farnaz Fallah-Arani, Thomas Conlan, Celine Trouillet, Hugh Goold, Laurent Chorro, Barry Flutter, Terry K. Means, Frédéric Geissmann and Ronjon Chakraverty. (2011) Langerhans Cells Regulate Cutaneous Injury by Licensing CD8 Effector Cells Recruited to the Skin. Blood. 117: 7063-7069. *Corresponding author. (Pubmed)
Kordula Kautz-Neu, Madelon Noordegraaf, Stephanie Dinges, Clare L. Bennett, Dominik John, Björn E. Clausen and Esther van Stebut. (2011) Langerhans cells are negative regulators of the anti-Leishmania response. J. Exp. Med. 208: 885-91. (Pubmed)
Hugh D. Goold, David Escors, Thomas J. Conlan, Ronjon Chakraverty and Clare L. Bennett. (2011) Conventional DC are required for the activation of helper-dependent CD8 T cell responses to a model antigen after cutaneous vaccination with lentiviral vectors. J. Immunol. 186: 4565-4572. (Pubmed)
Eduardo Fernandes, Hugh D Goold, Adrien Kissenpfennig, Bernard Malissen, Julian Dyson and Clare L Bennett. (2010) The Role of Direct Presentation by Donor Dendritic Cells in Rejection of Minor Histocompatibility Antigen-Mismatched Skin and Hematopoietic Cell Grafts. Transplantation. 91: 154-60. (Pubmed)