The role of idiotype-specific immunity in antigen receptor diversity

Millar, David George (2010). The role of idiotype-specific immunity in antigen receptor diversity. University of Birmingham. Ph.D.

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Abstract

Lymphocytes express antigen receptors which are formed by re-arrangement of gene segments. Mutations acquired during this process, predominantly in the complementarity determining regions (CDRs), result in generation of non-germline sequences. Through analysing the CDR3 sequence, this study attempts to determine whether editing of the lymphocyte repertoire is present in an HLA-dependant manner.

Data presented demonstrates a decrease frequency of CDR3-derived HLA-A2 binding peptides in HLA-A2+ donors (0.03% (SYFPEITHI) and 0.35% (BIMAS)) compared with HLA-A2- donors (0.24% (SYFPEITHI, p=0.01) and 0.54% (BIMAS, p=0.19)). Trends similar to those seen in HLA-A2 were observed in other HLA alleles as well suggesting that there may be a process by which potentially dangerous B cell populations are edited from the B cell repertoire. Similar analysis of the TCR CDR3 did not reveal any such process in all of the HLA alleles tested suggesting that there is no immunoediting of the T cell repertoire.

Simultaneously, this study attempts to determine the processing and presentation of CDR3-derived peptides at the cell surface using lymphocyte antigen receptor models containing CDR3-encoded viral epitopes. The apparent presence of these peptides on the cell surface leads to the hypothesis that antibodies enter the antigen processing pathway and potentially deliver an immunogenic peptide to a target cell. Using antibodies specific for B cells, this study has shown that cells labelled with an antibody-peptide complex are targeted and lysed by cytotoxic CD4+ T cells in a peptide-specific manner. The use of such technology in antibody immunotherapy may be of considerable therapeutic benefit.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):