Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Avinash Bhandoola

Abstract

T-cell production depends on the recruitment of hematopoietic progenitors into the thymus. T cells are among the last of the hematopoietic lineages to recover after bone marrow transplantation (BMT), but the reasons for this delay are not well understood. We have found that rare bone marrow progenitors that can efficiently repopulate the thymus are poorly reconstituted for at least 4 weeks and intrathymic progenitor niches remain unsaturated for at least 10 weeks after BMT. In the following studies, we show that thymic recovery is limited by the number of progenitors entering the thymus after BMT. Under normal physiologic conditions, thymic settling is selective and either CCR7 or CCR9 is required for progenitor access into the thymus. The mechanisms of early thymic reconstitution after BMT, however, are unknown. Here we report that thymic settling is briefly CCR7/CCR9-independent after BMT but continues to rely on the selectin ligand PSGL-1. The CCR7/CCR9 independence is transient, and by 3 weeks after BMT these receptors are again strictly required. We next examine homing of progenitors to the thymus using an assay in which we analyze the thymus for donor-derived thymocytes as early as 22 hours. For unirradiated mice, we determined that LMPP and CLP can each directly home to the thymus. Surprisingly, following irradiation conditioning, we find homing to the thymus decreases more than 10-fold. Concurrently, an important chemokine ligand for thymic homing, CCL25, is greatly reduced on endothelium. Finally, we show that pretreatment of bone marrow progenitors with CCL25 and CCL21 partially restores homing to the thymus after irradiation conditioning and promotes T cell reconstitution.

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