Identification of molecular and cellular mechanisms in autoimmune disease
As co-Director of the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory (DIL), I am focused on understanding the molecular and cellular mechanisms mediating autoimmune syndromes such as type 1 diabetes (T1D). We aim to identify and characterise the function of genes that contribute to disease susceptibility in both humans and nonobese diabetic (NOD) mice. Some T1D-associated genes and molecular pathways are shared by humans and mice as exemplified by the CTLA-4 and IL-2 pathways. Both CTLA-4 and IL-2 are required for the function of FOXP3+CD25+CD4+ regulatory T cells (Tregs), a T cell subset that dampens the immune response and is less functional in T1D patients and NOD mice. Tregs are a therapeutic target in T1D and the subject of intense investigation by many laboratories, including the DIL.
To link the gene variants that cause autoimmune disease with their biological effects within the immune system, we study the peripheral blood of T1D patients and healthy volunteers accessed through the NIHR Cambridge BioResource. Genotypes at T1D-causal genes are correlated with phenotypes ranging from mRNA and protein expression of the disease-causing gene to parameters of immune cell activation and differentiation. One phenotype for which we have discovered a genotype correlation is the expression of CD25 (the α subunit of the IL-2 receptor) on memory CD4+ T cells, which contributes to the homeostatic levels of IL-2 required for maintaining the functional activity of Tregs. This genotype is also associated with Treg activation in response to IL-2. Another phenotype for which we have discovered a genotype correlation is the expression of CTLA-4 in FOXP3+CD25+CD4+ Tregs; donors with a genotype conferring protection from T1D have higher CTLA-4 expression. We and our collaborators have been characterising these crucial regulatory cells in detail at the cellular and molecular levels with the aim of increasing their activity by administering ultra-low-dose IL-2 to T1D patients. To understand the effects of IL-2 in these patients, we have optimised methods to obtain Tregs directly from small amounts of blood and assess the methylation status of genes critical for the maintenance and function of Tregs.
L. Esposito, K. M. Rainbow, J. Clark, D. B. Rainbow, H. Stevens, J. Denesha, S. Duley, S. Dawson, G. Coleman, S. Nutland, G. L. Bell, C. Moran, M. Pekalski, J. A. Todd and L. S. Wicker. Investigation of soluble and Tm-CTLA-4 isoforms in serum and microvesicles. J. Immunol., in the press (2014).
Pekalski, M. L., R. C. Ferreira, R. M. R. Coulson, A. J. Cutler, H. Guo, D. Smyth, K. Downes, C. A. Dendrou, X. Castro-Dopico, L. Esposito, G. Coleman, H. Stevens, S. Nutland, N. M. Walker, C. Guy, D. B. Dunger, C. Wallace, T. I. M. Tree, J. A. Todd and L. S. Wicker. Post-thymic expansion in human CD4 naive T cells defined by expression of functional high affinity IL-2 receptors. J. Immunol. 190, 2554–2566 (2013).
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Rainbow, D. B., C. Moule, H. I. Fraser, J. Clark, S. K. Howlett, O. Burren, M. Christensen, V. Moody, C. A. Steward, J. P. Mohammed, M. E. Fusakio, E. L. Masteller, E. B. Finger, J. P. Houchins, D. Naf, F. Koentgen, W. M. Ridgway, J. A. Todd, J. A. Bluestone, L. B. Peterson, J. Mattner and L. S. Wicker. Evidence that Cd101 is an autoimmune diabetes gene in NOD mice. J. Immunol. 187, 325–336 (2011).
Dendrou, C.A., V. Plagnol, E. Fung, J. H. M. Yang, K. Downes, J. D. Cooper, S. Nutland, G. Coleman, M. Himsworth, M. Hardy, O. Burren, B. Healy, N. M. Walker, K. Koch, W. H. Ouwehand, J. R. Bradley, N. J. Wareham, J. A. Todd, and L. S. Wicker. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature Genet. 41, 1011–1015 (2009).
Araki, M., D. Chung, S. Lui, D. B. Rainbow, G. Chamberlain, V. Garner, K. M. Hunter, L. Vijayakrishnan, L. B. Peterson, M. Oukka, A. H. Sharpe, R. Sobel, V. K. Kuchroo and L. S. Wicker. Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in NOD mice. J. Immunol. 183, 5146–5157 (2009).
Ridgway, W.M., B. Healy, L.J. Smink, D. Rainbow and L.S. Wicker. New tools for defining the ‘genetic background’ of inbred mouse strains. Nature Immunol. 8, 669–673 (2007).
Yamanouchi, J., D. Rainbow, P. Serra, S. Howlett, K. Hunter, V.E.S. Garner, A. Gonzalez-Munoz, J. Clark, R. Veijola, R. Cubbon, S.L. Chen, R. Rosa, A.M. Cumiskey, S. Gregory, J. Rogers, P.A. Lyons, B. Healy, L.J. Smink, J.A. Todd, L.B. Peterson, L.S. Wicker* and P. Santamaria*. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nature Genet. 39, 329–337 (2007). *share senior authorship
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