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Title: T-cell receptor repertoire sequencing in health and disease
Author: Heather, J. M.
ISNI:       0000 0004 8502 1790
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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The adaptive immune systems of jawed vertebrates are based upon lymphocytes bearing a huge variety of antigen receptors. Produced by somatic DNA recombination, these receptors are clonally expressed on T- and B-lymphocytes, where they are used to help detect and control infections and help maintain regular bodily function. Full understanding of various aspects of the immune system relies upon accurate measurement of the individual receptors that make up these repertoires. In order to obtain such data, protocols were developed to permit unbiased amplification, high-throughput deep-sequencing, and error-correcting bioinformatic analysis of T-cell receptor sequences. These techniques have been applied to peripheral blood samples to further characterise aspects of the TCR repertoire of healthy individuals, such as V(D)J TCR gene usage and pairing distributions. A large number of sequences are also found to be shared across multiple individuals, including sequences matching receptors belonging to known and proposed T-cell subsets making use of invariant rearrangements. The resolution provided also permitted detection of low-frequency recombination events that use unexpected gene segments, or contained alternative splicing events. Deep-sequencing was further used to study the effect of HIV infection, and subsequent antiretroviral therapy, upon the TCR repertoire. HIV-patient repertoires are typified by marked clonal inequality and perturbed population structures, relative to healthy controls. The data presented support a model in which HIV infection drives expansion of an subset of CD8+ clones, which -- in combination with the virally-mediated loss of CD4+ cells -- is responsible for driving repertoires towards an idiosyncratic population with low diversity. Moreover these altered repertoire features do not significantly recover after three months of therapy. Deep-sequencing therefore presents opportunities to investigate the properties of TCR repertoires both in health and disease, which could be useful when analysing a wide variety of immune phenomena.
Supervisor: Chain, B. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available