The evaluation of human de novo T cell production is critical for a better understanding of T cell homeostasis and the immune reconstitution processes. The presence of a functional thymus post-puberty has been unsuspected due to the paucity of tools. This thesis provides direct evidence for a functional thymus, which can contribute to the diversity of the immune reconstitution in pathological situations where the immune system is severely destroyed. Through peripheral blood PCR-based quantification of TCR alpha and beta rearrangement excision/deletion circles (TREC), by-products of gene rearrangement events, we demonstrated that a diversified de novo T cell production occurs throughout life, even though thymic function decreases with age. De novo T cell production remains intact following allogenic hematopoietic stem cell transplantation (AHSCT) in the absence of graft-versus-host disease (GVHD) and therefore a reduced thymus function cannot be responsible for the long-lasting reduction in peripheral blood naive T cells observed in transplanted patients. As naive T cells from AHSCT patients have reduced levels of IL-7Ralpha chain (CD 127) expression, we propose that their low frequencies reflect an impaired naive T cell survival rather than thymic dysfunction as signaling through CD127 was previously reported to upregulate Bcl-2 expression. Evidence gathered in this thesis supports the concept that such naive T cells try to replenish themselves through enhanced levels of proliferation but fail to do so and likely die in the process. / Monitoring of the peripheral alpha and beta TREC ratio, a marker of intrathymic proliferation, demonstrated that HIV infection either induces the cellular depletion or inhibits the cell cycling of differentiating thymocytes. As intrathymic proliferation is important for both the magnitude and diversity of thymic function, the results of this thesis indicate that the replenishment of the naive T cell peripheral compartment through de novo T cell production is both quantitatively and qualitatively limited in HIV-infected individuals leading to the contraction of the peripheral T cell repertoire. / Although peripheral blood quantification of alpha and beta TREC can estimate peripheral blood RTE frequencies, reflective of thymopoiesis levels, it does not constitute a method that can lead to the characterization of this important T cell subset. To better understand the biology of RTEs, we engineered a transgene with restricted GFP expression in T cell that recently rearranged their TCR. This model would be very useful for the identification of molecules capable of modulating thymic function as well as serving as a source for obtaining a highly purified population of RTEs, then allowing the characterization of their gene expression profile. / Taken together, this thesis demonstrates the contribution of the adult thymus to immune reconstitution following AHSCT and during HIV infection.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84415 |
| Date | January 2002 |
| Creators | Poulin, Jean-François, 1974- |
| Contributors | Sekaly, Rafick-Pierre (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001973895, proquestno: AAINQ88558, Theses scanned by UMI/ProQuest. |
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