Role of lipid-specific T cells in human inflammation and translational development of new therapies to treat allergic disease
Supervisor: Prof Graham Ogg
Atopic and allergic diseases affect up to 20-30% of the UK population and have considerable associated morbidity, mortality and health economic burden for individuals and the NHS. Atopic eczema is a disease with complex genetic and environmental susceptibility factors. Whilst it is likely that many loci are involved, the association of filaggrin null mutations with atopic eczema implicates events in the skin as having a crucial primary role in disease pathogenesis. We have recently made the observation that lipid-specific, CD1a-retsricted T cells may play a major role in human skin inflammation in the presence of filaggrin null mutations. We have recruited a cohort of adult 40 individuals with atopic eczema that have been followed for over 5 years with extensive longitudinal data including clinical, IgE, circulating peptide antigen-specific T cell frequencies and filaggrin genotype and phenotype. We will take acute lesional and non-lesional skin samples from 20 individuals with atopic dermatitis (10 with filaggrin mutations and 10 without common European filaggrin null mutations) and skin from 10 non-atopic controls. We will also examine lesional and non-lesional skin, 5 days after allergen skin challenge from these individuals, which we have also established in Oxford. Briefly, the lesional infiltrate will be investigated for lipid-specific CD1a-restricted T cells using flow cytometry and functional assays which are already established. We will relate these findings to filaggrin genotype and expression and the existing clinical and laboratory data on the cohort. The influence of the innate and adaptive cell populations on epithelial function will be examined using microarray analysis together with rtPCR and Western Blot; and the underlying mechanisms will be investigated using recombinant cytokines and relevant antibodies.
This translational project is based at the Weatherall Institute of Molecular Medicine, within the MRC Human Immunology Unit. There are excellent core facilities, infrastructure and expertise readily available. The student would receive training in molecular and cellular immunology techniques including cell culture, functional assays (ELISpot, intracellular FACS staining, bead array) and HLA tetrameric complex staining. In addition the student would gain experience in handling human skin biopsies and growing keratinocytes, with concomitant assays including imaging, microarray, rtPCR and Western Blot. The student would also learn about regulatory issues surrounding the use and storage of human samples including ethics, hospital R&D, GCP and HTA. The student would attend GCP, statistical courses and relevant conferences and would also be able to attend the WIMM Techniques course which covers broad scientific techniques, as well as the excellent internal and guest speaker programmes available in the Weatherall Institute of Molecular Medicine.
McPherson T, Sherman VJ, Aslam A, Crack L, Chan H, Lloyd-Lavery A, Jones L, Ardern-Jones M, Ogg G. Filaggrin null mutations associate with increased frequencies of allergen-specific CD4+ Th2 cells in patients with atopic eczema. Br J Dermatol 2010;163:544-9.
Ogg G. Role of T cells in the pathogenesis of atopic dermatitis. Clin ExpAllergy2009;39(3):310-6.
Ardern-Jones M, Black A, Bateman E, Ogg G. Bacterial superantigen facilitates epithelial presentation of antigen to Th2 cells. Proc Natl Acad Sci U S A 2007;104:5557-5562.
Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38(4):441-6.
- de Jong A, Cheng TY, Huang S, Gras S, Birkinshaw RW, Kasmar AG, Van Rhijn I, Peña-Cruz V, Ruan DT, Altman JD, Rossjohn J, Moody DB. CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat Immunol. 2014 Feb;15(2):177-8
6. Bourgeois EA, Subramaniam S, Cheng TY, De Jong A, Layre E, Ly D, Salimi M, Legaspi A, Modlin RL, Salio M, Cerundolo V, Moody DB, Ogg G. Bee venom processes human skin lipids for presentation by CD1a. J Exp Med. 2015 Feb 9;212(2):149-63.
For further information please contact: Prof Graham Ogg