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Title: Expression, regulation and function of lectin-like transcript 1 (LLT1)
Author: Llibre, Alba
ISNI:       0000 0004 6495 4372
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Receptor-ligand pairs of C-type lectin-like proteins have been shown to orchestrate and modulate immune responses within particular immune cell subsets or in distinct body locations. The function of CD161 and Lectin-Like Transcript 1 (LLT1) has not been extensively studied, partially due to the lack of validated anti-LLT1 antibodies. Here, I characterised two novel anti-LLT1 monoclonal antibodies (2H7 and 7G7). Using them for flow cytometric and immunohistological staining, I characterised the expression of LLT1 in different healthy human tissues and found that LLT1 levels were particularly high in immune-privileged sites. Germinal centres (GC) are microanatomical structures that are critical for the development of high-affinity antibodies and B cell memory. They are organised into two zones, light and dark, with coordinated roles controlled by local signalling. LLT1 protein is known to be expressed on B cells, but its functional role in the GC reaction has not been explored. I found high expression of LLT1 on GC-associated B cells, early plasmablasts and GC- derived lymphomas. LLT1 expression was readily induced via BCR, CD40 and CpG stimulation on B cells. Ubiquitous expression of CD161 on Follicular Dendritic Cells (FDCs) was revealed, as well as on a subset of T follicular cells. Triggering of LLT1 supported B cell activation, CD83 upregulation and Chemokine (C-X-C Motif) Receptor 4 (CXCR4) downregulation, which is consistent with a role in drivingtransition from a dark to a light zone phenotype. Overall, these data suggest that LLT1-CD161 interactions play a novel and important role in B cell maturation within the GC in humans. A deep understanding of the GC reaction and the process of B cell selection could provide invaluable knowledge into effective vaccine design, generation of auto-antibodies and malignant transformation.
Supervisor: Willberg, Christian B. ; Klenerman, Paul ; Phillips, Rodney E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available