Intrathymic expression of Flt3 ligand enhances thymic recovery after irradiation

Abstract

Hematopoietic stem cell transplantation (HSCT) requires conditioning treatments such as irradiation, which leads to a severely delayed recovery of T cell immunity and constitutes a major complication of this therapy. Currently, our understanding of the mechanisms regulating thymic recovery is limited. It is known that a subpopulation of bone marrow (BM)-derived thymic immigrant cells and the earliest intrathymic progenitors express the FMS-like tyrosine kinase 3 (Flt3) receptor; however, the functional significance of this expression in the thymus is not known. We used the BM transplant model to investigate the importance of Flt3 ligand (FL) for the regeneration of the T cell compartment. We show that FL is expressed in the adult mouse thymus on the surface of perivascular fibroblasts. These cells surround the proposed thymic entry site of Flt3 receptor-positive T cell progenitors. After irradiation, perivascular FL expression is up-regulated and results in an enhanced recovery of thymic cellularity. Thymic grafting experiments confirm an intrathymic requirement for FL. Collectively, these results show that thymic stromal cell-mediated FL-Flt3 receptor interactions are important in the reconstitution of thymopoiesis early after lethal irradiation and HSCT, and provide a functional relevance to the expression of the Flt3 receptor on intrathymic T cell progenitors.