The activation of NK cells is mediated through specific interactions between activation receptors and their respective ligands. Little is known, however, about whether costimulation, which has been well characterized for T cell activation, occurs in NK cells. To study the function of NKG2D, a potential NK costimulatory receptor, we have generated two novel hamster mAbs that recognize mouse NKG2D. FACS analyses demonstrate that mouse NKG2D is expressed on all C57BL/6 IL-2-activated NK (lymphokine-activated killer (LAK)) cells, all splenic and liver NK cells, and ∼50% of splenic NKT cells. Consistent with limited polymorphism of NKG2D, its sequence is highly conserved, and the anti-NKG2D mAbs react with NK cells from a large number of different mouse strains. In chromium release assays, we show that stimulation of NK cells with anti-NKG2D mAb can redirect lysis. Also, enhanced lysis of transfected tumor targets expressing NKG2D ligand could be inhibited by addition of anti-NKG2D mAb. Interestingly, stimulation of LAK cells via NKG2D alone does not lead to cytokine release. However, stimulation of LAK via both an NK activation receptor (e.g., CD16, NK1.1, or Ly-49D) and NKG2D leads to augmentation of cytokine release compared with stimulation through the activation receptor alone. These results demonstrate that NKG2D has the ability to costimulate multiple NK activation receptors.

Summary In contrast to virtually all other tissues, the anatomy of differentiation in the bone marrow (BM) remains unknown. This is due to a lack of strategies to examine blood cell production in situ, which are required to understand differentiation, lineage commitment decisions, and define how spatial organizing cues inform tissue function. Here we developed approaches to image myelopoiesis and generated atlases of granulocyte and monocyte/dendritic cell differentiation. Granulopoiesis and dendritic/monopoiesis localize to different sinusoids and display lineage-specific spatial and clonal architectures. Acute systemic L. monocytogenes infection induces lineage-specific progenitor clusters through increased progenitor self-renewal, but the different lineages remain spatially separated. Monocyte dendritic cell progenitors (MDP) map with Ly6C lo monocytes and conventional dendritic cells; these localize to a subset of vessels expressing a major regulator of myelopoiesis 1 colony-stimulating-factor 1 (CSF1/ M-CSF). Specific deletion of Csf1 in endothelium disrupted the architecture around MDP and their localization to sinusoids. Subsequently, there were reduced MDP numbers and differentiation ability, and loss of Ly6C lo monocytes and dendritic cells during homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for specific spatial organization of definitive hematopoiesis.

Highlights d Pregnancy primes CD8 + T cells with fetal specificity that persists after pregnancy d Memory CD8 + T cells are cytolytic and primed for effector cytokine production d Fetal-specific CD8 + T cells are functionally exhausted during secondary pregnancy d PD-1 and LAG-3 suppress CD8 + T cells selectively with fetal antigen re-stimulation

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Under axial loading conditions with an intact fibula, both IMN and LP provide stable fixation. There was no advantage to the use of an ASN over a standard IMN. IMN resulted in the highest stiffness, load to failure, and failure energy for OTA type 43.A3 fractures with as little as 3 cm of distal bone stock.

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