There exists controversy over the nature of haematopoietic progenitors of T cells. Most T cells develop in the thymus, but the lineage potential of thymus-colonizing progenitors is unknown. One approach to resolving this question is to determine the lineage potentials of the earliest thymic progenitors (ETPs). Previous work has shown that ETPs possess T and natural killer lymphoid potentials, and rare subsets of ETPs also possess B lymphoid potential, suggesting an origin from lymphoid-restricted progenitor cells. However, whether ETPs also possess myeloid potential is unknown. Here we show that nearly all ETPs in adult mice possess both T and myeloid potential in clonal assays. The existence of progenitors possessing T and myeloid potential within the thymus is incompatible with the current dominant model of haematopoiesis, in which T cells are proposed to arise from lymphoid-. Our results indicate that alternative models for lineage commitment during haematopoiesis must be considered.

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...

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells.

Primary neonatal Th1 cells develop alongside of Th2 upon priming of the newborn but undergo apoptosis upon recall with antigen. These Th1 cells were isolated, and their death was correlated with elevated IL-13Ralpha1 chain expression. Strikingly, neutralization of Th2s' IL-4 reduced apoptosis, sustained recall responses, and the live Th1 cells displayed a decrease in IL-13Ralpha1 expression. Blockade of IL-13Ralpha1 or IL-4Ralpha also restores recall and secondary Th1 responses. Adult T cells primed within the neonatal environment did not upregulate IL-13Ralpha1 chain or undergo apoptosis and developed recall Th1 responses. These observations indicate that developmental expression of IL-13Ralpha1 along with IL-4Ralpha provides a receptor through which IL-4 induces death of Th1 cells and skews neonatal immunity toward Th2.