HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage.

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Presentation transcript:

HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

Thymopoiesis Thymus TN3 HSC TN4 TN2 TN1 Myeloid Erythroid CMP Common Myeloid Progenitor CD3-CD4-CD8- (TN, 3-5%) CD4+CD8+ CD4+ CD8+ Common Lymphoid Progenitor CLP

HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

PROPERTIES OF PLURIPOTENTIAL HEMATOPOIETIC STEM CELLS Self-Renewal Differentiation

Dick, J Nature 423: HSC Self-Renewal and Differentiation

Weissman, I.L Science 287: Phenotypic Characteristics of HSC

FACS Profile of HSC

Dorshkind, K Annu. Rev. Immunol. 8:

HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

Specification versus Commitment

Akashi et al Nature. 404: Expression of Transcription Factors During Hematopoiesis

Busslinger, M Curr. Opinion Immunol. 12: Expression of Pax5 is Required for B Lymphopoiesis

Where Should Branchpoints Be Drawn?

HSC CMP Common Lymphoid Precursor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

FACS Resolution of CMP and GMP

HSC CLP CMP Multipotentl Lymphoid Precursor proB GMPMEP Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte Common Lymphoid Progenitor CD45R CD43 IgM immaturemature IgD Myelopoiesis preB ETP CD4+ CD8+ Thymus Granulocyte Macrophage Progenitor Megakaryocyte Erythrocyte Progenitor

Adolfsson et al. Cell 121:295, 2005 Lin- Sca-1+ c-kit+ Flt3+ cells Have B, Granulocyte, and Macrophage Developmental Potential

HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

Adolfsson et al. Cell 121:295, 2005 Lin- Sca-1+ c-kit+ Flt3+ cells Have B, Granulocyte, and Macrophage Developmental Potential

Adolfsson et al. Cell 121:295, 2005 Lin- Sca-1+ c-kit+ Flt3+ cells Lack Erythroid andMegakaryocyte Developmental Potential

Adolfsson J. et al. Cell 121:295, 2005 Alternative Models of Hematopoiesis

HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

Identification of bone marrow CLP

Kondo et al. Cell :

Notch and T Cell Development MacDonald H.R Trends in Immunol. 22:

Radtke, F. et al Immunity 10:

Thymopoiesis Thymus TN3 HSC TN4 TN2 TN1 Myeloid Erythroid CMP Common Myeloid Progenitor CD3-CD4-CD8- (TN, 3-5%) CD4+CD8+ CD4+ CD8+ Common Lymphoid Progenitor CLP

Based on Allman et al., Nat. Immunol. 4:168, 2003 Isolation of ETP by FACS

Models of Early Thymopoiesis Bhandoola et al. J. Immunol 171:5653, 2003

HSC CMP Common Lymphoid Progenitor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Hematopoiesis IgM IgD CLP

FETAL HEMATOPOIESIS

HSC CMP Common Lymphoid Precursor proB preB B CD4- CD8- CD4+ GMPMEP CD8+ Thymus Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte CD4+ CD8+ immature Adult Hematopoiesis IgM IgD CLP

HSC CMP GMP MEP Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte Fetal Hematopoiesis B IgM Pro-B Pre-B Macrophage B/f

Fetal Hematopoiesis Godin and Cumano Nat. Rev. Immunol. 2: 593, 2002

Quail Chick

Fetal Hematopoiesis Godin and Cumano Nat. Rev. Immunol. 2: 593, 2002

Dzierzak E. et al Immunol. Today 19:

Gekas et al. Developmental Cell 8:365, Identification of Hematopoietic Stem Cells in the Placenta

Fetal Adult Fetal RBC Myeloid Cells gd T cells B-1 B Cells Adult RBC Myeloid Cells B2 B Cells Fetal Hematopoiesis

B1 B2 B1 and B2 B Cells IgM IgM high CD5+/- CD11b CD45R IgD low IgD high Serous Cavities (peritoneum); self- renewing; function in innate immunity Spleen and Lymph Nodes; Produced throughout life; function in adaptive immunity

Fetal Liver B-1 B Cells B2 B Cells Adult Bone Marrow

Adapted from Rothstein TL. J. Immunol. 168:4257, 2002 Models of B1 B Cell Development LineageSelection B1 Progenitor B1 Precursor B2 Progenitor B2 Precursor B1 B2 ? B2 Progenitor B2 Precursor BCR signals

I. B Cell Development: Recent History

Carvalho TL et al. J.Exp. Med. 194:1141, 2001 B Cell Development In IL-7 -/- Mice

Carvalho TL et al. J.Exp. Med. 194:1141, 2001 B-1 B Cells Are Present In IL-7 -/- Mice

AGM Placenta Melchers, F. Nature 277:219, 1979 d9-11 Paige et al.,J. Exp. Med. 150:548, 1979 d8 Owen, Cooper, & Raff. Nature 249:361, 1974 d12 Solvason et al. Int. Immunol. 3:543, 1991 d13 Velardi, A. and M. Cooper. J. Immunol. 133:672, d14 Appearance of B Lineage Cells During Embryogenesis Godin, I. et al. PNAS. 92:773, 1995 d8

AGM Placenta Solvason et al. Int. Immunol. 3:543, 1991 d13 Appearance of B Lineage Cells During Embryogenesis

Milne CD et al. Immunol. Rev. 197:75, 2004 Regulation of B Lymphopoiesis By IL-7 and TSLP IL-7 TSLP

Giliani, S. et al. Immunol. Rev. 203:110, 2005 The IL-7 and TSLP Receptors IL-7R TSLPR aga

Vosshenrich et al. PNAS 101:11070, 2004 B1 B Cell Numbers Are Reduced In Mice That Fail to Express IL-7Ra

HSC CMP GMP MEP Common Myeloid Progenitor Hematopoietic Stem Cell Granulocyte Macrophage Erythrocyte Megakaryocyte Fetal Hematopoiesis B IgM Pro-B Pre-B Macrophage B/f

Effects of Aging on Hematopoiesis

Embryogenesis Senescence

CD4 + CD8 + T cells B CELLS Memory B cells Activation Germinal center reaction MZ B cells Skewed V H repertoire T CELLS Memory T cells Activation Oligoclonal dominance Cytokine production Effector generation Thymus Bone Marrow IgM + B cells Aging Spleen Primary and secondary follicle with germinal center Periarteriolar lymphoid sheath MZ B Cells Exit of IgM+ cells T cell production Antibody-forming cells Aging