Role of CD1a-restricted T cells in human inflammation and translational development of new therapies to treat allergic disease
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-restricted T cells may play a major role in human skin inflammation in the presence of filaggrin null mutations.
We have recruited a cohort of 40 adult 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.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.
|1||de Jong A, Peña-Cruz V, Cheng TY, Clark RA, Van Rhijn I, Moody DB. 2010. CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire.Nat. Immunol., 11 (12), pp. 1102-9. - http://www.ncbi.nlm.nih.gov/pubmed/21037579|
|2||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. 2014. CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens.Nat. Immunol., 15 (2), pp. 177-85. - http://www.ncbi.nlm.nih.gov/pubmed/24362891|
|3||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. 2015. Bee venom processes human skin lipids for presentation by CD1a.J. Exp. Med., 212 (2), pp. 149-63. - http://www.ncbi.nlm.nih.gov/pubmed/25584012|
|4||Subramaniam S, Aslam A, Misbah SA, Salio M, Cerundolo V, Moody DB, Ogg G. 2016. Elevated and cross-responsive CD1a-reactive T cells in bee and wasp venom allergic individuals.Eur. J. Immunol., 46 (1), pp. 242-52. - http://www.ncbi.nlm.nih.gov/pubmed/26518614|
|5||Jarrett R, Salio M, Lloyd-Lavery A, Subramaniam S, Bourgeois E, Archer C, Cheung KL, Hardman C, Chandler D, Salimi M, Gutowska-Owsiak D, Bernardino de la Serna J, Fallon PG, Jolin H, Mckenzie A, Dziembowski A, Podobas EI, Bal W, Johnson D, Moody DB, Cerundolo V, Ogg G. 2016. Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.Sci Transl Med, 8 (325), pp. 325ra18. - http://www.ncbi.nlm.nih.gov/pubmed/26865566|
Cheung KL, Jarrett R, Subramaniam S, Salimi M, Gutowska-Owsiak D, Chen YL, Hardman C, Xue L, Cerundolo V, Ogg G. Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a. J Exp Med. 2016 Oct 17;213(11):2399-2412. PubMed PMID: 27670592