Superantigens trigger the polyclonal activation of human T cells. We exploited this property to gain insight into the mechanisms governing CD4 T cell expansion and to study the functional heterogeneity of naive and memory CD4 T cell subsets. We show that the amount of TCR ligand affects the evolution of a T cell response in two ways: by shaping the diversity of the T cell population recruited in the proliferative pool and by affecting the progression of these precursors into cell cycle. These two processes characterize a hierarchy of recruitment of cells that strongly correlates with the efficiency of TCR engagement but not with the relative precursor frequency in the non-immune repertoire. Remarkably, once established, the distribution of T cell clones within a selected repertoire is maintained by the characteristic of T cells to expand at a rate that is independent of quantitative differences in ligand exposure. Moreover, at optimal ligand concentrations that lead to the simultaneous expansion of all responsive T cell clones, we observed a marked clone-specific heterogeneity in the capacity to secrete cytokines. The functional heterogeneity of different CD4+ T cell subpopulations was also studied using a superantigen model. Based on the expression of CD45RA and CCR7, four distinct subsets of CD4+ T lymphocytes can be identified: naive (CD45RA+ CCR7+), central memory (TCM, CD45RA- CCR7+), effector memory (TEM, CD45RA- CCR7-) and a previously uncharacterized subset (CD45RA+ CCR7-). In CD8 T cells, this subset has been shown to comprise "terminally differentiated" effector memory cells. The four subsets show different functional sensitivities for the superantigens, the TEM population being the most sensitive and the naive cells being the least sensitive, as measured by the upregulation of activation markers. We show that the CD4+ CD45RA+CCR7- subpopulation, which is rarely detectable in healthy individuals, is enriched in T cells having str
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84235 |
| Date | January 2004 |
| Creators | Dumont, Alain |
| 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: 002030985, proquestno: AAINQ98241, Theses scanned by UMI/ProQuest. |
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