Reader in Haemato-Immunology
DC and LC biology - DC immunotherapy.
Dendritic cells (DC) are specialised immune cells that link innate and adaptive immunity. In the skin they function in co-operation with other immune cells, including Langerhans cells (LC), the unique macrohage population of the epidermis, and other myeloid and lymphoid populations in the dermis. Together these cells work together to maintain skin immune homeostasis.
Our key research goals are to gain a greater understanding of LC and DC development and function within the skin, and how these processes become dysregulated in cancer and as a result of immune pathology. We use this knowledge to develop new ways of harnessing DC for immunotherapy.
Projects in the lab include:
1. Defining the plasticity and function of skin myeloid cells in 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 and LC populations.
Control of effector T cell function by LC
LC are born as tissue resident macrophages, but differentiate into cells that are functionally and transcriptionally similar to DC. One of our key challenges in our lab over many years has been to define the function of LC. We use models of bone marrow transplantation and GVHD to address this question. In collaboration with Ronjon Chakraverty in IIT we have demonstrated that conventional recipient DC populations are required to activated donor T cells, but that the function and survival of allo-reactive T cells is determined by the tissue in which they ultimately reside. In the skin epidermis, direct interaction with LC results in the programming of pathogenic T cells, which become resident within the skin. Thus different DC/LC populations interact with donor T cells at temporally and spatially distinct phases of the T cell response, and LC are required to license T cell function in situ in the epidermis. On-going work is aimed at defining the molecular nature of this interaction.
Defining repair of the LC network and restoration of immune homeostasis after immune injury
GVHD results in the killing of host allo-reactive cells in the skin, including LC. We are interested in understanding how immune homeostasis is re-established in the skin after GVHD, and the effect this has on cutaneous immune responses to infection and allergens.We have shown that immune injury leads to replacement of the resident LC network by monocyte-derived cells that became functionally and transcriptionally indistinguishable from the cells they replace. On-going work is aimed at defining how short-lived monocytes can become long-lived LC within the epidermal environment.
Immune injury due to GVHD also leads to long-term disruption of the dermal myeloid cell compartment. We are investigating how these changes impacts on pathology and immune function in the skin.
2. Harnessing DC for cancer immunotherapy
The development of T cell immunotherapies has revolutionised our approach to treating cancer. However, despite this many patients and cancers do not respond, and there is a need to build on this success to improved treatment outcomes. DC are essential for T cell-mediated rejection of tumours, but we still know little about how DC may work with T cells to promote tumour destruction after immunotherapy.
Lentiviral vectors are potent vaccination vehicles, and we have show that this is partly due the direct- and cross-presentation of lentivirus-encoded antigens by DC. Projects in the lab are aimed at understanding the cross-talk between DC and T cells in tumours and how this interaction changes in the context of adoptive T cell transfer of checkpoint blockade. We also seek to target DC with lentivectors in combinatorial strategies to enhance T cell immunotherapy in poorly-responsive tumours.
- Selected publications
- Ferrer IR, West HC, Henderson S, Ushakov DS, Santos E Sousa P, Strid J, Chakraverty R, Yates AJ, Bennett CL. A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury. Sci Immunol. 2019 Aug 23;4(38). pii: eaax8704. doi: 10.1126/sciimmunol.aax8704. PubMed PMID: 31444235.
- Hotblack A, Holler A, Piapi A, Ward S, Stauss HJ, Bennett CL. Tumor-Resident Dendritic Cells and Macrophages Modulate the Accumulation of TCR-Engineered T Cells in Melanoma. Mol Ther. 2018 Jun 6;26(6):1471-1481. doi: 10.1016/j.ymthe.2018.03.011. Epub 2018 Mar 16. PubMed PMID: 29628306; PubMed Central PMCID: PMC5986719.
- Santos E Sousa P, Ciré S, Conlan T, Jardine L, Tkacz C, Ferrer IR, Lomas C, Ward S, West H, Dertschnig S, Blobner S, Means TK, Henderson S, Kaplan DH, Collin M, Plagnol V, Bennett CL, Chakraverty R. Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease. JCI Insight. 2018 Mar 8;3(5). pii: 97011. doi: 10.1172/jci.insight.97011. PubMed PMID: 29515032; PubMed Central PMCID: PMC5922296.
- Galleu A, Riffo-Vasquez Y, Trento C, Lomas C, Dolcetti L, Cheung TS, von Bonin M, Barbieri L, Halai K, Ward S, Weng L, Chakraverty R, Lombardi G, Watt FM, Orchard K, Marks DI, Apperley J, Bornhauser M, Walczak H, Bennett C, Dazzi F. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci Transl Med. 2017 Nov 15;9(416). pii: eaam7828. doi: 10.1126/scitranslmed.aam7828. PubMed PMID: 29141887.
- West HC, Bennett CL. Redefining the Role of Langerhans Cells as Immune Regulators within the Skin. Front Immunol. 2018 Jan 5;8:1941. doi: 10.3389/fimmu.2017.01941. eCollection 2017. Review. PubMed PMID: 29379502; PubMed Central PMCID: PMC5770803.
- Hotblack A, Seshadri S, Zhang L, Hamrang-Yousefi S, Chakraverty R, Escors D, Bennett CL. Dendritic Cells Cross-Present Immunogenic Lentivector-Encoded Antigen from Transduced Cells to Prime Functional T Cell Immunity. Mol Ther. 2017 Feb 1;25(2):504-511. doi: 10.1016/j.ymthe.2016.11.001. PubMed PMID: 28153097; PubMed Central PMCID: PMC5368353.
- Sivakumaran S, Henderson S, Ward S, Sousa PS, Manzo T, Zhang L, Conlan T, Means TK, D'Aveni M, Hermine O, Rubio MT, Chakraverty R, Bennett CL. Depletion of CD11c⁺ cells in the CD11c.DTR model drives expansion of unique CD64⁺ Ly6C⁺ monocytes that are poised to release TNF-α. Eur J Immunol. 2016Jan;46(1):192-203. doi: 10.1002/eji.201545789. Epub 2015 Nov 30. PubMed PMID:26464217; PubMed Central PMCID: PMC4722854.
- Bennett CL, Fallah-Arani F, Conlan T, Trouillet C, Goold H, Chorro L, Flutter B, Means TK, Geissmann F, Chakraverty R. Langerhans cells regulate cutaneous injury by licensing CD8 effector cells recruited to the skin. Blood. 2011 Jun 30;117(26):7063-9. doi: 10.1182/blood-2011-01-329185. Epub 2011 May 12. PubMed PMID: 21566096; PubMed Central PMCID: PMC3336775.
- Bennett CL, van Rijn E, Jung S, Inaba K, Steinman RM, Kapsenberg ML, Clausen BE. Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity. J Cell Biol. 2005 May 23;169(4):569-76. Epub 2005 May 16. PubMed PMID: 15897263; PubMed Central PMCID: PMC2171694.
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