Dr Peter J Dyson

Dyson Group

Department of Immunology, Division of Medicine, Imperial College London

Aims i. -To understand the principles guiding selection of the T cell repertoire and how this is perturbed in genetic backgrounds which predispose to autoimmunity

The major genetic determinant of autoimmunity is encoded in the MHC region by the highly polymorphic class I and II loci. The products of these genes function both to select the T cell repertoire during T cell development in the thymus and to present (endogenous and exogenous) antigen to peripheral T cells. The importance of MHC in predisposition to autoimmunity has been known for several decades yet its molecular basis remains obscure. The general hypothesis underlying our research is that genetic predisposition to autoimmunity encoded by MHC alleles (class I and II) operates by influencing the balance of effector and regulatory potential within the repertoire of T cells. We are using various transgenic and retrogenic (retroviral modification of haematopoietic stem cells) approaches to gain insight into the processes which mould the T cell repertoire. Natural regulatory T cells (nTreg) play a key role in protecting against autoimmunity and we are currently defining disease associated changes of the T cell receptor repertoire within this T cell population. We are also exploring how the T cell repertoire is influenced by genetically determined defects in signal transduction pathways downstream of the T cell receptor which are strongly linked with predisposition to autoimmunity.

ii -To develop strategies for manipulating the balance of antigen specific T cell immunity/tolerance for clinical application in immunotherapy.

Genetic modification of T cells for adoptive immunotherapy is a promising clinical approach for influencing the balance of tolerance and immunity to control autoimmunity, protect transplants from rejection and to promote anti-tumour responses. One example from our Group is the introduction of the transcription factor Foxp3 into naive T cells using a retroviral vector. The transduced T cells acquire regulatory activity and can protect transplants from rejection. These two research strands bridge basic and applied immunology and are providing mutual insight into the adaptive immune response.

Selected Recent Publications

Monk, N., Roseanna, J., Hargreaves, E. J., Marsh, J., Sacks, S. H., Millrain, M., Simpson, E., Dyson, P. J. and Jurcevic, S. Anti-CD40L antibody effects are Fc region dependent: selective depletion of activated T cells rather than co-stimulation blockade. Nature Medicine 9 (2003), 1275-1280.

Quaratino, S., Badami, E., Pang, Duddy, Y., Bartok, I., Dyson, J., Kioussis, D. and Londei, M and Maiuri, L. Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mic. Nature Medicine. 10 (2004) 920-926

Silk, J. D., Schoendorf, D. S., Bartok, I., Chai, J-G., Gray, D.,Gray, Simpson. E. and Dyson, J. Unstable, Mixed-Haplotype MHC Class II Molecules Select a Small, Distinct and Functional CD4+ T Cell Repertoire. Molecular Immunology (2005) 42:1129-1139

Chai, J.-G., Xue, S. A., Coe, D., Addey, C., Bartok, I., Scott, D., Simpson, E., Stauss, H., Hori, S., Sakaguchi, S., and Dyson J. Regulatory T cells, derived from naive CD4+CD25- T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance. Transplantation (2005) 79:1310-1316

Ferreira, C., Furmanski, A., Millrain, M., Bartok, I., Guillaume, P., Lees, R., Simpson, E., MacDonald, H. R. and Dyson P. J. TCR-alpha CDR3 loop audition regulates positive selection. J. Immunol. (2006) 177: 2477-85

Pennington, D., Silva-Santos, B., Silberzahn, T., Escorcio-Correia, M., Woodward, M., Roberts, S., Smith, A., Dyson, P. J. and Hayday, A. Early events in the thymus affect the balance of effector and regulatory T cells. Nature (2006) 444: 1073-1077

Savage, P., Millrain, M., Dimokou, S., Stebbing, J. and Dyson, J. Expansion of CD8 cytotoxic T cells in vitro and in vivo using MHC class I tetramers. Tumour Biology (2007) 28:70-6.

Robertson, H. J., Chai, J.-G., Millrain, M., Scott, D., Hashim, H., Manktelow, E., Lemonnier, F., Simpson, E. and Dyson, J. Natural regulation of immunity to minor histocompatibility antigens. J Immunol. (2007) 178:3558-65

Rowbotham, N. J., Hager-Theodorides, A. L., Cebecauer, M., Shah, D. K., Drakopoulou, E., Dyson, J., Outram, S. V. and Crompton, T. Hedgehog signaling modulates TCR signal strength in thymus repertoire selection and T cell activation. Blood (2007) 109:3757-66

Weng, L., Dyson, J. and Dazzi, F. Low intensity transplant regimens facilitate recruitment of donor specific regulatory T cell which promote hematopoietic engraftment. PNAS (2007) 104:8415-20

Furmanski, A. L., Ferreira, C., Bartok, I., Dimakou, S., Rice, J., Stevenson, F., Millrain, M., Simpson, E.. and Dyson, J. Public T Cell Receptor Beta Chains are not Advantaged During Positive Selection. J. Immunol. In press