Transcript Document

Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Progenitor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
Thymopoiesis
CD8+ CD3-CD4-CD8CD4+
(TN, 3-5%)
Common
Myeloid
Progenitor
CMP
CD4+CD8+
Myeloid
Erythroid
HSC
44-25+
44+25+
CLP
44+25-
Common
Lymphoid
Progenitor
TN2
TN3
44-254+
TN4
4+8+
8+
TN1
Thymus
Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Progenitor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
PROPERTIES OF PLURIPOTENTIAL
HEMATOPOIETIC STEM CELLS
Differentiation
Self-Renewal
HSC Self-Renewal and
Differentiation
Dick, J. 2003. Nature 423:231-232
Phenotypic Characteristics of HSC
Weissman, I.L. 2000. Science 287:1442-1446
FACS Profile of HSC
Dorshkind, K. 1990. Annu. Rev. Immunol. 8:111-137.
Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Progenitor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
Specification versus Commitment
Expression of Transcription Factors During
Hematopoiesis
Akashi et al. 2000. Nature. 404:193-197.
Expression of Pax5 is Required
for B Lymphopoiesis
Busslinger, M. 2000. Curr. Opinion Immunol. 12:151-158.
Where Should Branchpoints Be Drawn?
Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Precursor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
FACS Resolution of CMP and GMP
Myelopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Megakaryocyte
Erythrocyte
Progenitor
CD4+
Multipotentl
Lymphoid
Precursor
Common
Lymphoid
Progenitor
Thymus
ETP
CD8+
CD45R
CLP
IgM
CD43
proB
preB
immature
IgD
mature
Lin- Sca-1+ c-kit+ Flt3+ cells Have B,
Granulocyte, and Macrophage Developmental
Potential
Adolfsson et al. Cell 121:295, 2005
Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Progenitor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
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 et al. Cell 121:295, 2005
Alternative Models of Hematopoiesis
Adolfsson J. et al. Cell 121:295, 2005
Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Progenitor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
Identification of bone marrow CLP
Kondo et al. Cell 1999. 91:661-672.
Notch and T Cell Development
MacDonald H.R. 2001. Trends in Immunol. 22:155-160.
Radtke, F. et al.
1999. Immunity
10:547-558.
Thymopoiesis
CD8+ CD3-CD4-CD8CD4+
(TN, 3-5%)
Common
Myeloid
Progenitor
CMP
CD4+CD8+
Myeloid
Erythroid
HSC
44-25+
44+25+
CLP
44+25-
Common
Lymphoid
Progenitor
TN2
TN3
44-254+
TN4
4+8+
8+
TN1
Thymus
Isolation of ETP by FACS
Based on Allman et al., Nat. Immunol. 4:168, 2003
Models of Early Thymopoiesis
Bhandoola et al. J. Immunol 171:5653, 2003
Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Progenitor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
FETAL HEMATOPOIESIS
Adult Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Thymus
CD4+
CLP
CD4CD8-
Common
Lymphoid
Precursor
CD4+
CD8+
CD8+
IgM
proB
preB
immature
IgD
B
Fetal Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Macrophage
B/f
IgM
B
Pro-B
Pre-B
Fetal Hematopoiesis
Godin and Cumano Nat. Rev. Immunol. 2: 593, 2002
Chick
Quail
Fetal Hematopoiesis
Godin and Cumano Nat. Rev. Immunol. 2: 593, 2002
Dzierzak E. et al. 1998. Immunol. Today 19:228-236.
Identification of Hematopoietic Stem Cells in the
Placenta
Gekas et al. Developmental Cell 8:365, 2005.
Fetal Hematopoiesis
Fetal
Fetal RBC
Myeloid Cells
gd T cells
B-1 B Cells
Adult
Adult RBC
Myeloid Cells
B2 B Cells
B1 and B2 B Cells
CD45R
IgMhigh
B1
CD5+/CD11b
Serous Cavities
(peritoneum); selfrenewing; function in
innate immunity
IgDlow
CD45R
IgM
B2
IgDhigh
Spleen and Lymph Nodes;
Produced throughout life;
function in adaptive
immunity
Fetal Liver
B-1 B Cells
Adult Bone
Marrow
B2 B Cells
Models of B1 B Cell Development
Lineage
Selection
B1
Progenitor
B2
Progenitor
B2
Progenitor
B1
Precursor
B2
Precursor
B2
Precursor
BCR
signals
B1
B2
B1
?
B2
Adapted from Rothstein TL. J. Immunol. 168:4257, 2002
I. B Cell Development: Recent
History
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
Carvalho TL et al. J.Exp. Med. 194:1141, 2001
Appearance of B Lineage Cells During
Embryogenesis
Melchers, F. Nature 277:219,
1979 d9-11
Godin, I. et al. PNAS.
92:773, 1995 d8
Placenta
AGM
Velardi, A. and M.
Cooper. J.
Immunol. 133:672,
1984. d14
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
Appearance of B Lineage Cells During
Embryogenesis
Placenta
AGM
Solvason et al. Int.
Immunol. 3:543, 1991 d13
Regulation of B Lymphopoiesis By
IL-7 and TSLP
IL-7
TSLP
Milne CD et al. Immunol. Rev. 197:75, 2004
The IL-7 and TSLP Receptors
a g
IL-7R
a
TSLPR
TSLPR
Giliani, S. et al. Immunol. Rev. 203:110, 2005
B1 B Cell Numbers Are Reduced In Mice
That Fail to Express IL-7Ra
Vosshenrich et al. PNAS 101:11070, 2004
Fetal Hematopoiesis
Common
Myeloid
Progenitor
Granulocyte
Macrophage
GMP
CMP
Erythrocyte
Megakaryocyte
MEP
HSC
Hematopoietic
Stem
Cell
Macrophage
B/f
IgM
B
Pro-B
Pre-B
Effects of Aging on
Hematopoiesis
Embryogenesis
Senescence
IgM+
B cells
CD4+
CD8+
T cells
Thymus
T cell
production
Bone Marrow
Exit of IgM+ cells
Antibody-forming
cells
Spleen
Aging
Aging
Periarteriolar lymphoid
sheath
Aging
Aging
B CELLS
Memory B cells
Activation
Germinal center reaction
MZ B cells
Skewed VH repertoire
Primary and secondary follicle
with germinal center
T CELLS
Memory T cells
Activation
Oligoclonal dominance
Cytokine production
Effector generation
MZ B
Cells