Early T lineage progenitors (ETPs) in the thymus are thought to develop from common lymphoid progenitors (CLPs) in the bone marrow (BM). We compared thymic ETPs to BM CLPs in mice and found that they differed in several respects. Thymic ETPs were not interleukin 7 (IL-7)-responsive and generated B lineage progeny with delayed kinetics, whereas BM CLPs were IL-7-responsive and rapidly generated B cells. ETPs sustained production of T lineage progeny for longer periods of time than BM CLPs. Analysis of Ikaros-deficient mice that exhibit ongoing thymopoiesis without B lymphopoeisis revealed near-normal frequencies of thymic ETPs, yet undetectable numbers of BM CLPs. We conclude that ETPs can develop via a CLP-independent pathway.

Interleukin 17C (IL-17C) is a member of the IL-17 family that is selectively induced in epithelia by bacterial challenge and inflammatory stimuli. Here we show that IL-17C functioned in a unique autocrine manner, binding to a receptor complex consisting of the receptors IL-17RA and IL-17RE, which was preferentially expressed on tissue epithelial cells. IL-17C stimulated epithelial inflammatory responses, including the expression of proinflammatory cytokines, chemokines and antimicrobial peptides, which were similar to those induced by IL-17A and IL-17F. However, IL-17C was produced by distinct cellular sources, such as epithelial cells, in contrast to IL-17A, which was produced mainly by leukocytes, especially those of the T(H)17 subset of helper T cells. Whereas IL-17C promoted inflammation in an imiquimod-induced skin-inflammation model, it exerted protective functions in dextran sodium sulfate-induced colitis. Thus, IL-17C is an essential autocrine cytokine that regulates innate epithelial immune responses.

Signaling by the transmembrane receptor Notch is critical for T lineage development, but progenitor subsets that first receive Notch signals have not been defined. Here we identify an immature subset of early T lineage progenitors (ETPs) in the thymus that expressed the tyrosine kinase receptor Flt3 and had preserved B lineage potential at low progenitor frequency. Notch signaling was active in ETPs and was required for generation of the ETP population. Additionally, Notch signals contributed to the subsequent differentiation of ETPs. In contrast, multipotent hematopoietic progenitors circulated in the blood even in the absence of Notch signaling, suggesting that critical Notch signals during early T lineage development are delivered early after thymic entry.

To generate T cells throughout adult life, the thymus must import hemopoietic progenitors from the bone marrow via the blood. In this study, we establish that thymus settling is selective. Using nonirradiated recipient mice, we found that hemopoietic stem cells were excluded from the thymus, whereas downstream multipotent progenitors (MPP) and common lymphoid progenitors rapidly generated T cells following i.v. transfer. This cellular specificity correlated with the expression of the chemokine receptor CCR9 by a subset of MPP and common lymphoid progenitors but not hemopoietic stem cells. Furthermore, CCR9 expression was required for efficient thymus settling. Finally, we demonstrate that a prethymic signal through the cytokine receptor fms-like tyrosine kinase receptor-3 was required for the generation of CCR9-expressing early lymphoid progenitors, which were the most efficient progenitors of T cells within the MPP population. We conclude that fms-like tyrosine kinase receptor-3 signaling is required for the generation of T lineage-competent progenitors, which selectively express molecules, including CCR9, that allow them to settle within the thymus.

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...

Genetic inactivation of Notch signaling in CD4−CD8− double-negative (DN) thymocytes was previously shown to impair T cell receptor (TCR) gene rearrangement and to cause a partial block in CD4+CD8+ double-positive (DP) thymocyte development in mice. In contrast, in vitro cultures suggested that Notch was absolutely required for the generation of DP thymocytes independent of pre-TCR expression and activity. To resolve the respective role of Notch and the pre-TCR, we inhibited Notch-mediated transcriptional activation in vivo with a green fluorescent protein–tagged dominant-negative Mastermind-like 1 (DNMAML) that allowed us to track single cells incapable of Notch signaling. DNMAML expression in DN cells led to decreased production of DP thymocytes but only to a modest decrease in intracellular TCRβ expression. DNMAML attenuated the pre-TCR–associated increase in cell size and CD27 expression. TCRβ or TCRαβ transgenes failed to rescue DNMAML-related defects. Intrathymic injections of DNMAML− or DNMAML+ DN thymocytes revealed a complete DN/DP transition block, with production of DNMAML+ DP thymocytes only from cells undergoing late Notch inactivation. These findings indicate that the Notch requirement during the β-selection checkpoint in vivo is absolute and independent of the pre-TCR, and it depends on transcriptional activation by Notch via the CSL/RBP-J–MAML complex.

SummaryThe interleukin-17 (IL-17) cytokines, IL-17A to IL-17F, are emerging as critical players in host defence responses and inflammatory diseases. Substantial data support the role of these proteins in innate and adaptive immunity. Of these family members, IL-17A, IL-17F and IL-17E have been the best studied. Both IL-17A and IL-17F contribute to the host response to extracellular bacteria and fungi, and IL-17E has been shown to play a role in parasitic infections. In addition, numerous pre-clinical and clinical studies link these proteins to the pathogenesis of inflammatory diseases, and a number of therapeutic programmes targeting these family members are in clinical development. This review will highlight the cellular sources, receptors/target cells, and role in inflammation of these and the less-characterized family members, IL-17B, IL-17C and IL-17D.

Lin-SCA1 + KIT hi FLT3 + (LSKFLT3 +) • Found in the bone marrow • IL-7Rα-CD44 hi VCAM1 + and IL-7Rα-/low CD44 hi VCAM1-subsets 19,20,56, 68,69 ELP Lin-SCA1 + KIT hi FLT3 + (LSKFLT3 +) • Found in the bone marrow • A lymphoid-specified subset of MPPs that are RAG + CD44 hi and GFP + in RAG-GFP reporter mice 74,75 L-selectin-expressing MPP (LSP) Lin-SCA1 + KIT hi L-selectin-expressing and THY1.1-in THY1.1 strains of mice • Found in the bone marrow • An L-selectin-expressing subset of MPPs that are FLT3 + CD44 hi 78 CLP Lin-SCA1 low AA4 + IL-7Rα + KIT low • Found in the bone marrow • FLT3 + CD44 hi 22,23 CLP-2 (also known as pre-pro-B cell) IL-7Rα + B220 + CD19-KIT-/low and human CD25 + in pTα-reporter mice • Found in the bone marrow • FLT3 + CD43 + CD44 hi 27,57 ETP Lin low KIT hi CD25-• Found in the thymus • IL-7Rα-/low CD4 low CD44 hi SCA1 + • FLT3 + and FLT3-subsets • CD24-(also known as DN1a) and CD24 + (also known as DN1b) subsets 25,46-50, 52,55 DN2 cell Lin low CD25 + KIT hi • Found in the thymus • IL-7Rα + CD4 low CD44 hi 33,34,124 CLP, common lymphoid progenitor; CMLP, common myelo-lymphoid progenitor; DN2, double-negative 2; ELP, early lymphoid progenitor; ETP, early T-cell progenitor; FLT3, fms-related tyrosine kinase 3; GFP, green fluorescent protein; HSC, haematopoietic stem cell; IL-7Rα, interleukin-7 receptor α-chain; Lin, lineage; LMPP, lymphoid-primed multipotent progenitor; L-selectin, lymphocyte selectin; MPP, multipotential progenitor; pTα, pre-T-cell receptor α-chain; pTα-reporter mice, mice that express human CD25 under the control of locus control elements of the gene encoding pTα. RAG, recombination-activating gene; SCA1, stem-cell antigen 1; VCAM1, vascular cell-adhesion molecule 1. 252 | MARCH 2006 | VOLUME 6 www.nature.com/reviews/immunol E R R AT U M