T lymphopoiesis requires settling of the thymus by bone marrow-derived precursors throughout adult life. Progenitor entry into the thymus is selective, but the molecular basis of this selectivity is incompletely understood. The chemokine receptor CCR9 has been demonstrated to be important in this process. However, progenitors lacking CCR9 can still enter the thymus, suggesting a role for additional molecules. Here we report that the chemokine receptor CCR7 is also required for efficient thymic settling. CCR7 is selectively expressed on bone marrow progenitors previously shown to have the capacity to settle the thymus, and CCR7 ؊/؊ progenitors are defective in settling the thymus. We further demonstrate that CCR7 sustains thymic settling in the absence of CCR9. Mice deficient for both CCR7 and CCR9 have severe reductions in the number of early thymic progenitors, and in competitive assays CCR7 ؊/؊ CCR9 ؊/؊ double knockout progenitors are almost completely restricted from thymic settling. However, these mice possess nearnormal thymic cellularity. Compensatory expansion of intrathymic populations can account for at least a part of this recovery. IntroductionAll blood lineages are derived from hematopoietic stem cells (HSCs) in the bone marrow (BM). Unlike other blood lineages, T cells continue the majority of their development outside the BM, in the thymus. As the thymus does not contain self-renewing progenitors, it must import BM-derived precursors during adult life. [1][2][3][4][5] This process can be regarded as 3 steps: generation of T-lineage progenitors in the BM, mobilization of progenitors out of the BM into the blood, and settling of blood-borne progenitors into the thymus. Thymic settling progenitors (TSPs) have not yet been definitively identified due to their presumed rarity. [6][7][8][9] After thymic settling, TSPs generate Lineage-marker (Lin)-negative, Kit ϩ CD25 -early thymic progenitors (ETPs), which constitute the earliest defined T-cell precursor population within the thymus. 4,10 ETPs in turn undergo proliferative expansion to give rise to CD4 -CD8 -Kit ϩ CD25 ϩ double-negative 2 (DN2) and CD4 -CD8 -Kit lo CD25 ϩ DN3 cells. DN3 cells undergo additional proliferation before differentiating into CD4 ϩ CD8 ϩ double-positive (DP) cells, which constitute the majority of thymocytes. DP thymocytes subsequently undergo T-cell receptor-dependent selection to generate CD4 or CD8 single-positive (SP) cells, which emigrate from the thymus to populate the periphery. 11 The BM contains multiple progenitors with T-lineage potential that may contribute to T lymphopoiesis. [12][13][14][15] The most primitive hematopoietic progenitors in the BM have a Lin -Sca1 ϩ Kit ϩ (LSK) phenotype and can be differentiated into subsets on the basis of expression of the cytokine receptor Flt3. These subsets include multipotent and self-renewing HSCs (LSKFlt3 -), multipotent progenitors (MPPs), which do not possess self-renewal capacity (LSKFlt3 lo ), 16 and lymphoid-primed multipotent progenitors (LMPPs; LSKFlt3 hi ). 17 LM...

Recent reports describe hematopoietic abnormalities in mice with targeted instability of the mitochondrial genome. However, these abnormalities have not been fully described. We demonstrate that mutant animals develop an age-dependent, macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis. Mice die of severe fatal anemia at 15 months of age. Bonemarrow transplantation studies demonstrate that these abnormalities are intrinsic to the hematopoietic compartment and dependent upon the age of donor hematopoietic stem cells. These abnormalities are phenotypically similar to those found in patients with refractory anemia, suggesting that, in some cases, the myelodysplastic syndromes are caused by abnormalities of mitochondrial function. (Blood. 2009;114:4045-4053)

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...

The U.S. Food and Drug Administration (FDA) is the primary federal government agency that is responsible for protecting and promoting public health by assuring the safety, efficacy, and security of human and veterinary drugs, biologics, medical devices, food, dietary supplements, cosmetics, tobacco, and products that emit radiation. To achieve this mission, the FDA balances the twin goals of assuring products are safe and effective and encouraging innovation and new product entry into the market. As a science‐based institution, the FDA also reviews clinical research, monitors the marketing practices of regulated‐industry to assure the public gets accurate, science‐based information, and interacts with international bodies with the goal of reducing the burden of regulation and harmonizing regulatory requirements. The FDA's organization currently consists of the Office of the Commissioner and four directorates overseeing the core functions of the agency. Functionally, the FDA is comprised of six product centers: the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Veterinary Medicine (CVM), the Center for Devices and Radiological Health (CDRH), the Center for Food Safety and Applied Nutrition (CFSAN), and the Center for Tobacco Products (CTP). The FDA also has an office dedicated to research and multiple offices focused on global regulatory operations and policy. Collectively these Centers oversee the development, manufacture, promotion and distribution of drugs, biologics, veterinary products, medical devices, foods, dietary supplements, cosmetics, and tobacco in the United States under the Federal Food, Drug, and Cosmetic Act (FDCA) and its implementing regulations. This article provides a historical summary of the legal framework in which the FDA operates, discusses the FDA's organization and role, highlights the regulatory requirements for each of the product types the FDA regulates, and ends with a general discussion of the FDA's enforcement powers.