Schulz, Ruth Margaret;
(1995)
Tolerance status of transgenic mice expressing a major histocompatability complex class I molecule under the control of human CD2 regulatory elements.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
CD2Kb transgenic mice express the major histocompatibility complex class I (MHC I) gene, H-2Kb, under the control of regulatory elements from the human CD2 gene. As a result, H-2Kb is expressed on lymphoid and some myeloid cell lineages. The precise pattern of H-2Kb expression varies between CD2Kb lineages. In addition, CD2Kb lineages differ in terms of the number of H-2Kb molecules present on cell surfaces. These two factors, pattern and level of antigen expression, have profound effects on the induction of immunological tolerance towards the antigen. CD2Kb transgenic mouse lineages can be divided into two groups on the basis of their response to antigen in vivo. Mice from one line, CD2Kb-3, tolerate skin grafts from mice bearing H-2Kb molecules, but CD2Kb-3 T cells respond to H-2Kb in vitro. Mice from three other lines, CD2Kb-4, -7 and -11, rejected H-2Kb-bearing skin grafts. T cells from mice that had rejected grafts did not respond to in vitro H-2Kb stimulation by lysing H-2Kb-bearing target cells. Instead H- 2Kb-reactive cells expressed CD4 and recognised processed peptides from H-2Kb presented on host MHC class II (MHC II) molecules. The capacity of these CD2Kb mice to reject skin grafts correlates with absence of detectable H-2Kb expression on myeloid cell lineages. This implies that peptides derived from self-antigens not expressed by MHC II+ cells in vivo are not presented to thymocytes, allowing potentially self-reactive CD4+8- T cells to reach maturity. These studies demonstrate the importance of assessing the effect of altered self MHC expression on the entire T cell repertoire. From these studies we have discovered two completely distinct, apparently paradoxical situations. In one case tolerance of H-2Kb-bearing grafts coincides with in vitro responsiveness of CD8+ T cells. In the other case grafts are rejected due to recognition of a cryptic self antigen presented on MHC II as a result of processing endogenous peptides.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Tolerance status of transgenic mice expressing a major histocompatability complex class I molecule under the control of human CD2 regulatory elements |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10103057 |
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