Understanding the role of T cell cross-reactivity in human disease

Throughout life exposure to a vast array of pathogens shapes our immune system to establish a repertoire of specific memory T cells that can be rapidly recruited to combat secondary challenges from previously encountered pathogens. Whilst T cells provide essential immunosurveillance to combat and eliminate pathogenic assault, these heroes can turn into villains by mediating unwanted immune responses against self via T cell receptor (TCR) cross-reactivity. This cross-reactivity trigger is important in a number of human disorders (i.e. autoimmunity, allergy, cancer) and therapies for end-stage disease (i.e. transplantation). This project explores how the virus-specific T cell repertoire is able to recognise different human leukocyte antigens (HLA; human MHC) allotypes via TCR cross-reactivity. We have identified a cross-reactive CMV-specific T cell that recognises HLA-B27 allotypes that requires further functional characterisation to elucidate molecular interactions between the TCR/peptide/HLA complex (1,2). This recognition may underpin transplant rejection (3,4) and HLA-B27 associated autoimmune diseases such as ankylosing spondylitis, reactive arthritis, ulcerative colitis and autoimmune eye disease. You will be embedded in a start-of-the-art laboratory with access to the latest technology associated with the phenotypic and functional dissection of human T cell responses (various T cell assays, flow cytometry, RNASeq, TCRSeq), and interrogation of antigen processing and presentation (proteomics and mass spectrometry, gene editing technologies including CRISPR/Cas9). 1. Nguyen TH, Westall GP, Bull TE, Meehan AC, Mifsud NA*, Kotsimbos TC*. Cross-reactive anti-viral T cells increase prior to an episode of viral reactivation post human lung transplantation. PLoS ONE 2013;8(2):e56042 2. Nguyen TH, Rowntree LC, Pellicci DG, Bird NL, Handel A, Kjer-Nielsen L, Kedzierska K, Kotsimbos TC, Mifsud NA. Recognition of distinct cross-reactive virus-specific CD8+ T cells reveals a unique TCR signature in a clinical setting. J Immunol. 2014;192:5039-49. 3. Mifsud NA, Nguyen TH, Tait BD, Kotsimbos TC. Quantitative and functional diversity of cross-reactive EBV-specific CD8+ T cells in a longitudinal study cohort of lung transplant recipients. Transplantation 2010;90:1439-49 4. Rowntree LC, Nguyen TH, Gras S, Kotsimbos TC, Mifsud NA. Deciphering the clinical relevance of allo-human leukocyte antigen cross-reactivity in mediating alloimmunity following transplantation. Curr Opin Organ Transplant. 2016 Feb;21(1):29-39.