The thymus is a complex cellular structure made up of several interdependent cell types and is the primary site for T cell development. A population of fetal thymic epithelial cells (TEC), marked by MTS20 and MTS24, when grafted in vivo can generate a functional thymus containing all thymic epithelial cells and is capab,e of supporting T cell differentiation. Further analysis using in vivo grafting experiments have determined the endoderm as the sole origin for all major thymic epithelial subsets. These findings suggest the possibility that a bipotent thmic epithelial progenitor cell (TEPC) gives rise to both cortical and medullary epithelial compartments. The first ai of this study was to address whether bipotent mouse TEPC give rise to both medullary and cortical epithelial cell populations and to begin to establish a model of TEC differentiation through ontogeny. Its second aim was to start to define condidtions for maintaining functionally undifferentiated RTEPC in vitro. Finally, as little is knowth about the genetic regulation of human thymic development and TEC differentiation, I hve used comparative analysis to investigate the similaarities in expression of key regulations of thymus development between human and mouse, which will aid in the translation of mouse thmic research to human. the main findings of this thesis are i) that a bipotent thymic epithelial progenitor cell population that contribute to both medullary and cortical epithelial cell compartments exists in vivo, but is at low frequency even by E12.5. ii) That a unipotent progenitor population committed to a cortical epithelial cell fate is also present as early as E11.5. iii) That E11.5 TEC can be propagated in vitro in semi defined conditions, but appear to revert ro an early endodermal phenotype on prolonged culture and iv) that the genetic program regulating thymus organogenesis appears to be conserved between mouse and human. In addition I have defined the exact time of haematopoietic cell entry into the human thymus, and the time of entry of mesenchymal cells and the mesenchymal distribution pattern throughout human thymic ontogeny. I also establish the time of onset of differentiation and maturation of hTEC, and using known mouse TEPC markets, show the existence of a population of Claudin4+Ueal+ hTEC at week 8, presumed equivalent to the precursor cells for the AIRE1+ subpopulation of medullary TEC in the mouse.

acase@tulane.edu / Recent thymic emigrants (RTEs) are the youngest subset of peripheral T cells, which are known to differ in how they functionally contribute to the naïve T cell pool. This distinctive cell population is known to contribute to the maintenance of T cell receptor diversity in the peripheral T cell pool, but their involvement in combating chronic bacterial infections, such as typhoid fever, has not been explored. In the present study, we hypothesized that RTEs are essential contributors to the CD4 T cell response during persistent Salmonella Typhimurium infection, which predominantly relies on helper T cell immunity to control bacteria. To test this hypothesis we performed thymectomy or sham surgical treatment on mice, either prior to or during, an established, chronic Salmonella infection and measured disease outcomes. We found that thymic output is crucial in the formation of protective immune responses during the establishment of a Salmonella infection, but appears to be dispensable once the Salmonella infection is established. We found that thymectomy prior to infection resulted in increased infection-associated mortality, increased bacterial burdens and increased numbers of antigen-specific CD4+ T cells. Furthermore, it appears that thymectomized mice may be impaired in their ability to produce effector cytokines at early time points of infection, compared to thymically intact mice. In contrast, when thymectomy was performed 30 days after the initiation of Salmonella infection, there were no observable differences in survival, bacterial burdens or antigen-specific CD4+ T cell numbers through out infection. To directly study the contribution of RTEs to the Salmonella immune response, we developed an adoptive transfer model where purified RTEs could be transferred to a congenically marked host immediately prior to Salmonella infection and their responses could be tracked throughout infection. We found that RTEs are capable of proliferating and upregulating maturation markers in response to antigen; comparable to other mature, naïve CD4+ T cells. Together, these results may imply a unique role for thymic output and or recent thymic emigrants in the formation of early immune responses against a chronic, enteric pathogen like Salmonella. However, once the pathogen has disseminated systemically, thymic function does not appear to play a vital role in protective immune response. / 1 / James Alan Goggins

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Thesis (Ph. D.)--Virginia Polytechnic Institute, 1970. / Also available via the Internet.

Thesis (Ph. D.)--Cornell University, May, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 122-165). Available also in a digital version from Dissertation Abstracts.

Thesis (doctoral)--Kiel, 1982.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1964. / Typescript. Vita. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1969. / Typescript. Vita. Description based on print version record. Includes bibliographical references.

Thesis (M.S.)--University of Wisconsin--Madison, 1968. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.