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. 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. Despite the normalization of thymic settling signals, the rare bone marrow progenitors that can efficiently repopulate the thymus are poorly reconstituted for at least 4 weeks after BMT. Consistent with reduced progenitor input to the thymus, intrathymic progenitor niches remain unsaturated for at least 10 weeks after BMT. Finally, we show that thymic recovery is limited by the number of progenitors entering the thymus after BMT. Hence, T-lineage reconstitution after BMT is limited by progenitor supply to the thymus. (Blood. 2011;118(7): 1962-1970) IntroductionT cells provide critical immune protection from a range of pathogens. The T-lineage is the slowest to recover after irradiation and bone marrow transplantation (BMT), a delay that impairs immunologic protection of the host. 1 Peripheral T-cell reconstitution after BMT occurs through 2 mechanisms: one thymusindependent and one thymus-dependent. First, radioresistant host T cells and donor T cells provided in the graft homeostatically proliferate in the lymphopenic postirradiation environment. 2,3 Although this population expansion can partially correct numerical T-cell defects, the resulting cells are functionally compromised. 4,5 The functional recovery of the T-lineage relies on the second mechanism: the de novo generation of naive T cells in the thymus. 6,7 The generation of thymus-derived naive T cells can take years and is particularly slow in adults. 1,2,8 The reasons for this delay are not fully understood but have been suggested to involve impaired intrathymic development because of thymic stromal damage from conditioning regimens, age-related thymic involution, and graft-versus-host disease (GVHD). [9][10][11] The thymus does not contain self-renewing progenitors and therefore requires the importation of circulating bone marrow (BM)-derived progenitors to sustain thymopoiesis. [12][13][14] Thymic settling, however, is suggested to be a rare event, and the identity of thymic settling progenitors remains unclear. [15][16][17] All progenitors descend from hematopoietic stem cells (HSCs), which are phenotypically negative for lineage markers (Lin) and are additionally Kit ϩ Sca1 ϩ Flt3 Ϫ . Directly downstream of HSCs are nonrenewing multipotent progenitors (MPPs; Lin Ϫ Kit ϩ Sca1 ϩ Flt3 low ), 18 which in turn give rise to lymphoid-primed multipot...

T cell development requires periodic importation of hematopoietic progenitors into the thymus. The receptor-ligand pair P-selectin and P-selectin glycoprotein ligand 1 (PSGL-1) are critically involved in this process. In this study we examined the expression of functional PSGL-1 on BM hematopoietic progenitors. We demonstrate that functional PSGL-1 is expressed at low levels on hematopoietic stem cells, but upregulated on the cell surface of progenitors that bear other homing molecules known to be important for thymic settling. We found that progenitors able to home to the thymus expressed high levels of PSGL-1 transcripts compared to hematopoietic stem cells. We further demonstrate that hematopoietic progenitors lacking Fucosyltransferase 4 and 7 do not express functional PSGL-1, and do not home efficiently to the thymus. These studies provide insight into the developmentally regulated expression of a critical determinant involved in progenitor homing to the thymus.

Approximately one third of women who are diagnosed with malignant melanoma are of childbearing age. Therefore, it is not surprising that some studies have found malignant melanoma to be one of the most common malignancies diagnosed in pregnant women. The impact of pregnancy-related hormonal changes on melanoma development and progression remains controversial. Women undergo immunologic changes during pregnancy that may decrease tumor surveillance. Additionally, hormone receptors are found on some melanomas. Unfortunately, many of the past and even recent studies that have been published and are reviewed herein did not uniformly use appropriate control groups, account for confounding covariates, or employ appropriate statistical analysis, which makes it difficult to rely on the conclusions they reach. However, a review of the better controlled and preponderant studies demonstrates that pregnancy-associated melanomas are not associated with a poorer prognosis.