Bennett, CL

Chakraverty, R

Conlan, T

De Ascensao Santos e Sousa, P

Lomas, C

Means, TK

Plagnol, V

Shorrock, H

UCL Discovery

DC control of immunopathology: Interaction with tissue DC drives a unique transcriptional response in effector T cells  Pedro De Ascensao Santos E Sousa, Hannah Shorrock, Cara Lomas, Thomas Conlan, Terry K. Means, Vincent Plagnol, Ronjon Chakraverty* & Clare L Bennett*  Interactions between dendritic cells (DC) and primed effector T cells (Teff) within tissues have been shown to mediate the balance between control of disease and immunopathology.  In order to further investigate the role of tissue DC in driving CD8 Teff function, we adopted a systems biology approach.  We exploited a transplantation model in which monoclonal CD8+ T cells are transferred to antigen-mismatched recipients.  Teff were purified from lymphoid organs and peripheral tissues and their gene expression compared by hybridisation to the Affymetrix Gene 2.0 Array.  Computational analyses of these data demonstrate that Teff from lymphoid organs are transcriptionally distinct from those in peripheral tissues.  In particular, Teff in the skin and gut share a distinct gene signature, suggesting that specific interactions occurring at these sites are driving T cell function.  In the skin, expression of this signature is determined by the transition of T cells from the blood to the dermis then epidermis, the major site of skin pathology in this model. To investigate the role of tissue DC in driving the tissue signature of Teff, we used the Langerin-DTR mouse, from which epidermal Langerhans cells (LC) can be inducibly depleted in vivo.  Transcriptional profiling demonstrates that in the absence of LC the transition to expression of a full effector profile no longer occurs.  Correlation of genes differentially expressed by Teff in the LN, dermis and epidermis of LC-replete or -depleted mice with datasets from the Immunological Genome project (Immgen) showed that the epidermal datasets had the most differentially expressed genes.  These genes are significantly associated with coarse module 5 (C5), that is genes associated with T cell proliferation and changes in metabolic activity.  In summary we have used a systems biology approach to demonstrate that LC drive T cell-mediated immunopathology in the skin by switching on a transcriptional effector programme. 1. Bennett, C. L. & Chakraverty, R. Dendritic cells in tissues: in situ stimulation of immunity and immunopathology. Trends in immunology 33, 8-13 (2012). 2. Honda, T. et al. Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40, 235-247 (2014).     

DC control of immunopathology: Interaction with tissue DC drives a unique transcriptional response in effector T cells

http://discovery.ucl.ac.uk/1519763/1/De-Ascensao-Santos-e-Sousa_DC_control_immunopathology.pdf

DC control of immunopathology: Interaction with tissue DC drives a unique transcriptional response in effector T cells

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