Identifying chemokine receptor signals required for thymic settling (36.26)

Abstract

Abstract T cell generation requires the recruitment of bone marrow derived hematopoietic precursors to the thymus via the bloodstream. The chemokine receptor CCR9 and the selectin ligand PSGL-1 each independently support progenitor recruitment to the unirradiated thymus, but progenitors lacking each are not restricted from thymic entry. Hence, additional molecules are likely at work. We now show that the chemokine receptor CCR7 is also involved in this process, as CCR7-/- progenitors are impaired in thymic settling. Furthermore, mice lacking both CCR7 and CCR9 have severe reductions in the number of early intrathymic progenitors, and in competitive assays CCR7-/-CCR9-/- progenitors are almost completely restricted from thymic settling. The compensatory proliferation of rare intrathymic progenitors can allow CCR7-/-CCR9-/- thymi to achieve near-normal cellularity despite severely impaired settling by circulating progenitors. These studies, however, focused on the signals used in unirradiated mice. The mechanisms involved in reconstituting a lethally-irradiated thymus remain poorly defined. We found that during a brief period following irradiation, CCR7-/-CCR9-/- cells are now capable of thymic setttling. Together, these observations illustrate the critical role of chemokine receptor signaling in thymic settling and help to clarify the cellular identity of the physiologic thymic settling progenitors.