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Theses

CD4+ T cell homeostasis: the thymus, the cells and the environment

Abstract : The peripheral T cell number is under homeostatic control. Although T cells are produced daily in the thymus in significant numbers, and antigenic stimulation induces further T cell production through division, the peripheral T cell numbers are maintained constant. Thus, any newly produced T cell will only integrate the peripheral T cell pools if another T cell dies. In this way, the selection of the peripheral T cell repertoires is not only dependent on the interaction between each cell and its antigen but it is also dependent on interactions between different sub-populations of cells (Freitas and Rocha, 2000). In order to understand how peripheral T cell homeostasis is achieved, and to understand why is homeostasis attained at the observed equilibrium level, each of the contributing agents must be identified and the contribution of each determined.
T cells are originated in the thymus, resulting from a complex series of events. The thymic T cell production will be responsible throughout the lifetime of the organism for the daily export of newly generated T cells. However, the thymus involutes with age. This may have consequences for peripheral T cell homeostasis. Thus, the central T cell compartment should not be left out when peripheral T cell homeostasis is studied.
The peripheral T cell compartment comprises a number of smaller compartments, as not all T cells are born equal and many differentiate in the peripheral T cell pools into specific sub-populations with distinct proprieties and functions. The CD4+ and the CD8+ T cell subsets and the naïve, effector and memory compartments within the CD4+ and the CD8+ T cell compartments contribute differently for the individual's immunocompetence. Mechanisms involved in the control of the relative proportions of these sub-populations are also relevant for total T cell homeostasis.
The purpose of this thesis was to make advances in the understanding of the mechanisms responsible for peripheral T cell homeostasis in general and for peripheral CD4+ T cell homeostasis in particular. The studies were divided into three parts.
In the first part, the Thymus and its role in the maintenance of T cell numbers were evaluated. We developed a novel experimental system that allowed us to obtain a quantitative assessment of the fraction of competent pre-T cell precursors required to restore thymus function and also to evaluate the contribution of the thymus to the peripheral T cell pools. With the help of a mathematical model we were able to interpret the data obtained in order to demonstrate that there are no compensatory homeostatic mechanisms during thymic development and that the size of the peripheral total T cell pool is fairly independent of thymic output. Thus, peripheral mechanisms compensate for a lack of thymic output. When the naïve and activated/memory T cell compartments were analysed separately, we found that the naïve T cell compartment was more prone to reflect the size of the thymic SP compartment. Thus, we concluded that these compensatory mechanisms are more efficient in the generation of activated/memory T cells.
In the second part, the subject of research was the importance of peripheral T cell interactions for the establishment of peripheral T cell homeostasis. We have studied the interactions between the CD4+CD25+CD45RBlow T cells (the regulatory/suppressor CD4+ T cells) and CD4+CD25-CD45RBhigh T cells (naïve CD4+ T cells). We transferred these populations into immunodeficient hosts. We have observed that the ratio CD4+CD25+CD45RBlow to CD4+CD25-CD45RBhigh T cells present in the cells transferred was determinant for the numbers of cells recovered, and thus this interaction potentially determinant for peripheral T cell homeostasis. We have demonstrated this, re-introducing the CD4+CD25+ T cells in a mouse system (the CD25-/- BM chimeras) were the peripheral homeostasis is disturbed and this sub-population is absent. As we observed, the re-introduction of the CD4+CD25+ T cells in these BM chimeras had as a consequence the normalisation of the peripheral T cell pools. We have found proof that the presence of this sub-population is essential for the existence of homeostasis of the peripheral T cell numbers and thus, that peripheral T cell homeostasis is achieved also through sub-population structure.
In the third part of these studies, the importance of resources for the maintenance of the peripheral T cell sub-population structure was examined. Immediate candidates as resources are interleukins. The IL2-/- mice have reduced numbers of CD4+CD25+ T cells and develop autoimmune manifestations We postulated that the lack of IL2 was responsible for the decreased survival of the CD4+CD25+ regulatory T cells in the peripheral T cell pools, and thus that the autoimmune manifestations were again the consequence of a disruption in the peripheral sub-population structure, as these mice are devoid of this specific sub-population. We tested this hypothesis, by sorting the few CD4+CD25+ T cells present in the IL2-/- mice and testing these cells as suppressors in vivo. These cells proved to exert suppressor functions, suggesting that the IL2-/- mice are able to generate the CD4+CD25+ regulatory T cells. We confirmed this, by establishing BM chimeras using as donor BM cells a mixture of BM cells from IL2-/- and CD25-/- cells. These chimeras do not develop autoimmune manifestations and the peripheral T cell pools have the normal representation of the CD4+ T cell sub-populations, including the CD4+CD25+ T cells. Thus, the IL2-/- BM precursors were able to generate a viable population of regulatory T cells, as long as IL2 was present in the periphery. This illustrates the role of cytokines as resources with a major importance for the establishment of the observed peripheral sub-population structure.
Returning to the main subject of this thesis, our results allow us to state that the observed peripheral T cell homeostasis reflects not only the thymic production but also peripheral phenomena, and that these include interactions between different sub-popoulations. Underrepresented peripheral sub-populations, like the CD4+CD25+ regulatory T cells, play a major role in the maintenance of peripheral T cell homeostasis.
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https://tel.archives-ouvertes.fr/tel-00002017
Contributor : Afonso Almeida <>
Submitted on : Monday, November 25, 2002 - 5:28:50 PM
Last modification on : Monday, January 13, 2020 - 5:08:06 PM
Long-term archiving on: : Tuesday, September 11, 2012 - 6:45:15 PM

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  • HAL Id : tel-00002017, version 1

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Afonso Almeida. CD4+ T cell homeostasis: the thymus, the cells and the environment. Immunologie. Universidade do Porto, 2002. Français. ⟨tel-00002017⟩

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