National Jewish Health

About: National Jewish Health is a healthcare organization based out in Denver, Colorado, United States. It is known for research contribution in the topics: T cell & Asthma. The organization has 883 authors who have published 833 publications receiving 79201 citations. The organization is also known as: National Jewish Medical and Research Center.

Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function.

Abstract: MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 diversity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1d protein, which is essential to the development and function of natural killer T (NKT) cells. However, it remains unclear whether both CD1d isoforms are equivalent in their antigen presentation capacity and functions. Here, we report that CD1d2 molecules are expressed in the thymus of some mouse strains, where they select functional type I NKT cells. Intriguingly, the T cell antigen receptor repertoire and phenotype of CD1d2-selected type I NKT cells in CD1D1−/− mice differed from CD1d1-selected type I NKT cells. The structures of CD1d2 in complex with endogenous lipids and a truncated acyl-chain analog of α-galactosylceramide revealed that its A′-pocket was restricted in size compared with CD1d1. Accordingly, CD1d2 molecules could not present glycolipid antigens with long acyl chains efficiently, favoring the presentation of short acyl chain antigens. These results indicate that the two CD1d molecules present different sets of self-antigen(s) in the mouse thymus, thereby impacting the development of invariant NKT cells.

Pattern Recognition in Phagocytic Clearance of Altered Self

Abstract: Cells that are unnecessary or harmful to our body emerge in substantial numbers throughout our life. Such “unwanted” cells need to be promptly and selectively removed for tissue homeostasis to be maintained. Most of those cells are induced to undergo physiologic cell death, i.e., apoptosis, and subsequently eliminated by phagocytosis. Target selectivity in this phagocytosis reaction comes from the specific cell-cell interaction between phagocytes and dying cells. The surface structure of apoptotic cells is altered during the death pathway so that they become pattern recognizable as “altered self” by phagocytes, and such surface structures are sometimes called ACAMPs for apoptotic cell-associated molecular patterns. ACAMPs arise either from the exofacial exposure of endogenous molecules or the modification of preexisting surface molecules. Pattern-recognizing phagocytosis receptors present at the surface of phagocytes specifically bind, either directly or indirectly with an aid of bridge molecules, to ACAMPs and transmit signals to induce phagocytosis of bound apoptotic cells. Phagocytes often evoke subsequent actions, rather than simply digesting engulfed apoptotic cells, for a finer tuning of tissue homeostasis. In contrast, precise mechanisms and consequences of cells undergoing nonapoptotic death, i.e., necrosis or autophagy-related death, are less well understood.

Peptide selection by an MHC H-2Kb class I molecule devoid of the central anchor ("C") pocket.

Abstract: The peptide-binding site of the murine MHC class I molecule H-2Kb contains a deep C pocket, that is critical for peptide binding, as it accepts the anchor phenylalanine or tyrosine residue located in the middle (position 5, P5F/Y) of H-2Kb binding peptides. H-2Kb predominantly binds octameric peptides. By both criteria, H-2Kb is unique among the known murine and human class I molecules, none of which have a deep C pocket or preferentially select octamers. We investigated the relative importance of the C pocket in peptide selection and binding by the MHC. An MHC class I H-2Kb variant, KbW9, predicted to contain no C pocket, was engineered by replacing valine at MHC9 with tryptophan. This mutation drastically altered the selection of peptides bound to KbW9. The KbW9 molecule predominantly, if not exclusively, bound nonamers. New peptide anchor residues substituted for the loss of the P5F/Y:C pocket interaction. P3P/Y, which plays an auxiliary role in binding to Kb, assumed the role of a primary anchor, and P5R was selected as a new primary anchor, most likely contacting the E pocket. These experiments demonstrate that the presence of a deep C pocket is responsible for the selection of octameric peptides as the preferred ligands for Kb and provide insight into the adaptation of peptides to a rearranged MHC groove.

Hematopoietic Development of ES Cells in Culture

Abstract: Under appropriate culture conditions, ES cells will spontaneously differentiate and generate colonies known as embryoid bodies (EBs) that contain precursors of multiple lineages, including those of the hematopoietic system (1-7). Previous studies have demonstrated that the molecular events leading to hematopoietic commitment, as well as the kinetics of lineage development within the EBs, parallel that found in the normal mouse embryo (5). More recent studies (8-11) have supported these earlier findings and have provided evidence that hematopoietic development within EBs can be divided into the following distinct stages: hemangioblast, primitive and early definitive, and multilineage definitive. These stages most closely correspond to the preblood island, the early-mid yolk sac, and the late yolk sac-early fetal-liver hematopoietic programs within the mouse embryo.