This thesis presents studies on the interaction between the human T cell lymphotropic virus type 1 (HTLV-1) Tax protein and the 20S proteasome and the role of the interaction in cellular processes and the cytotoxic T cell (CTL) response against HTLV-1. The rapid translocation of Tax into the nucleus is described. Tax accumulates in the nucleus and forms unique bodies involved in transcriptional activation. It was further found that Tax associated with assembled nuclear 20S proteasomes and stimulated the chymotryptic and tryptic activities of the 20S proteasome, independent of the induction of the LMP2 and LMP7 proteasome subunits. Confocal microscopy revealed a partial colocalisation of Tax with nuclear proteasomes. A panel of Tax mutants was generated and their subcellular localisation and association with the 20S proteasome analysed. This analysis revealed that both the N- and C-terminus of Tax play a role in proteasome binding of Tax and further showed that proteasome binding was not sufficient for nuclear localisation of Tax. Therefore, Tax probably translocates into the nucleus prior to and independent of proteasome association. Tax specific CTL clones were generated and characterised using tetrameric MHC class I/peptide complexes. These CTL clones were used to investigate the requirements for processing and presentation of Tax for recognition by CTL. It was found that Tax was a metabolically very stable protein and that the presentation of the immunodominant Tax 11-19 epitope was dependent on the transporter associated with antigen presentation (TAP), independent of the expression of LMP2 and LMP7 proteasome subunits and resistant to treatment with the proteasome inhibitor lactacystin. It is proposed that the interaction between Tax and the 20S proteasome plays a role in Tax mediated transcriptional activation, leading to cellular activation and proliferation, and may not determine the immunodominance of Tax in the CTL response against HTLV-1.

Bibliography: leaves 197-274. / 274, [146] leaves, [9] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to characterize the cell-mediated immune response to Salmonella infection in mice, by comparing the antigen presenting cell activity of peritoneal cells (PCs) obtained from infected mice with that of PCs from normal mice and analysing the T cell subsets induced by primary and secondary Salmonella infections. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1993?

Thesis (doctoral)--Rijksuniversiteit te Utrecht.

Thesis (doctoral)--Rijksuniversiteit te Utrecht.

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliography.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Point mutations found in human breast cancer samples introduced into the Drosophila dco gene affect the Drosophila haematopoiesis. I described different haematopoietic phenotypes in such mutants and tested their connection with the Toll and the JAK/STAT signalling pathways.

In animals immunized with 2,4 dinitrophenyl (DNP) hapten-carrier protein conjugates, no in vitro cellular response is elicited by DNP, either alone, or when coupled to a heterologous carrier. In contrast, animals immunized with haptenic peptide-carrier conjugates do mount an in vitro cellular response towards the haptenic peptide. This apparent inconsistency led us to compare the in vivo and in vitro cellular immune responses to a synthetic peptide antigen and its DNP derivative to determine the activation specificity of the cells evoking this response. Guinea pigs were immunized with either the DNP substituted immunogen (DNP-N-10-C) or its unsubstituted form (N-10-C) and subsequent in vivo or in vitro cellular activation was evaluated for DNP alone, DNP coupled to the homologous determinant, and DNP coupled to heterologous carriers. The data suggests that in DNP-N-10-C immune guinea pigs, DNP substitution opens a new determinant exhibiting, in antigen reactive cells, a unique specificity towards the DNP moiety as well as a portion of the peptide to which it is conjugated. However the DNP group by itself does not have the configurational requirement to evoke cellular activation. It therefore plays a minor role in activation of the cellular immune response; the major contribution being supplied by the peptide portion of the 'shared' determinant. / Science, Faculty of / Microbiology and Immunology, Department of / Graduate

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