no IL-4 or IL-2secretion

?

CFU-MAST

IL-7 & Flt-3 Ligand(ref. 83)

To Bone Marrow

IL-6, SCF/c-kit Ligand (ref. 5)

Mouse Mφ = Kup�er Cell Formation

To Thymus

Committed Hematopoietic Cell

Mesodermal primitive macrophage Mφ in yolk sac

To Liver

Fetal Mφ

Kup�er Cell

Monoblast

(ref. 77,78,79)

F4/80+

F4/80+

HSA/CD24-

GM-CSF

M-CSF

ER-MP20+

CFU-GMER-MP12+Mφ

Mφ

INTRODUCTIONIn the fetus, committed hematopoietic stem cells develop in the mesoderm and migrate to the fetal liver in the 6th week of pregnancy. Fetal liver stem cells then initiate erythropoiesis and seed the developing thymus (in week 7) and bone marrow (in week 20).1-3 In the thymus, αβ and γδ T cells develop, and the potential also exists for various dendritic cells (DC) and natural killer (NK) cell types. In the bone marrow, B cells, granulocytes, monocytes and DC all potentially develop. This pattern persists well into adulthood.

B cell Development in Mouse; an exact parallel?

CD34+

CD43+

CD10+

CXCR4+

IL-7 Rα+

SCF R/ c-kit+

TdT+

Flt-3+

CD19-

CD24/ HSA-

CD25/ IL-2 Rα-

B cell Progenitor

CD34+/-

CD43+

CXCR4+

IL-7 Rα+

SCF R/ c-kit-

TdT+

Flt-3+

CD19-

CD24+/-

CD25-

CCR9+

Pre-Pro B cell (ref. 33,34,40)

CD43+

CXCR4+

IL-7 Rα+

SCF R/ c-kit+

TdT+

Flt-3+

CD19+

CD24+

CD25-

CCR9+

CXCR5+

Pro B cell(ref. 33,34,40)

CD43-

CXCR4+

IL-7 Rα+

SCF R/ c-kit+/-

TdT-

Flt-3-

CD19+

CD24+

CD25+

CCR9-

CXCR5+

Pre B cell(ref. 33,34,40)

CD43-

CXCR4+

IL-7 Rα-

SCF R/ c-kit-

TdT-

Flt-3-

CD19+

CD24+

CD25+

CD2+

CD72+

CCR9-

CXCR5+

ImmatureB cell (ref. 33,34,40)

PPBSF (ref. 35,36) IL-7 (ref. 37,41) TSLP (ref. 38,39)

Precursor

Langerhans Cell

Potential Langerhans Cell Developmental Pathway (abbreviated)17, 23

GM-CSFTNF-α

TGF-β

CD14-

CLA+

CD72+

CD11c+

CD1a+

CD34+

CD10+

CXCR4+

CD1a+

E-Cadherin+

Birbeck granule+

CD34++

CD38-

CD7-

CD44++

SCF R/c-kit+

Flt-3+ (ref. 1,2,3)

CD34++

CD38-

CD7+/-

CD44++

SCF R/c-kit+

Flt-3+

CD33+

CD43+

CD2-

CD10-

Thy-1/CD90+

CXCR4+/-

(ref. 1,4,5)

Fetal Liver Stem Cell

week 20

week 7

Proliferation

CD34++

CD38-

CD7+/-

CD44++

SCF R/c-kit+

CD33+

CD43+

CD2-

CD10-

CD90/Thy-1+

CXCR4++↑

FL83

CD34+ CD43+

CD10+ CD45RA+ CD90/Thy-1- TdT+ IL-7 Rα+

(ref. 30,31)

SDF-1

B-Lymphoid Progenitor

Pro-B cell /Pre-B-Ι cell (ref. 31,32)

Pre-B cell /Pre-B-ΙΙ cell (ref. 31,32)

Immature B cell (ref. 32)

Mature B cell (ref. 32)

CD34+ CD43+

CD10++↑ CD45RA+

TdT+ IL-7 Rα+/-

IL-7 & Flt-3 Ligand(ref. 83)

IL-3 (ref. 81,82)IL-7IL-3 (ref. 81,82)IL-7

CD40L (ref. 81)IL-3

CD40L (ref. 81)IL-3

CD10+ CD19+

IgM+ CD10+ CD19+ IgM+ IgD+

CD34+

CD4+

CD7-

CD3-

CD45RA-

(ref. 16)CD34+ CD4+ CD45RA+

CD34+

CD4+

CD45RA+

IL-3 Rα+

CD11c+

MHC-ΙΙ+

CD34++ CD38+ CD7++ CD44++ CD30lo

CD2+ CD5+ CD1a+ CD45RA++

CD34++

CD38+

CD7++

CD44+↓

CD33lo

CD2+

CD5+

CD1a-

CD45RA++↑

IL-7 Rα+

(ref. 4,6,7)

CD34+↓

CD38+

CD7+↓

CD44+

CD33-

CD2+

CD5+

CD1a+

CD45RA+↓

IL-7 Rα+

(ref. 6,7)

CD34-

CD38+

CD7+

CD44-

CD2+

CD5+

CD1a+

CD45RA-

CD4+

CD8α-

CD8β-

CD7+

CD2+

CD5+

CD1a+

CD45RA-

CD4+

CD8α+

CD8β-

(ref. 6,7)

CD7+

CD2+

CD5+

CD1a+

CD45RA-

CD45RO+

CD4+

CD8αβ+

CD69-

(ref. 6,7)

CD1a+

CD4+

CD8-

CD27-

CD45RA-

CD45RO+

CD69+

(ref. 6,7)

SCF/c-kit LigandGM-CSF IL-6

SCF/c-kit LigandGM-CSF IL-6

DeltaJaggedIL-7SCF/c-kit Ligand

CD34+ CD7++ IL-2 Rβ+ CD38+ CD161/NKRP1A+

(ref. 7,9,11)

CD34- CD7++

IL-2 Rβ+

CD161+

CD56+

(ref. 7,9,11)

CD16variable

CD2+ CD7++ IL-2 Rβ+ CD56+ (ref. 7,11)

CD56++

CD16-

SCF R/c-kit+

CD25+

MHC-ΙΙ+

IL-5 & IL-13 no IL-4secretion

SCF/c-kit LigandIL-2

CD56+

CD16++

SCF R/c-kit-

CD1a+

CD4+

CD8α/β+

CD69+

CD1a+

CD69+

CD27+

CD4+

CD8+

(ref 6,7)CD1a+

CD69+

CD27+

CD4-

CD8+

(ref 6,7)CD1a-

CD4+

CD8-

CD69+

CD45RA+

CD45RO-

CD27+

(ref. 6,7)

CD1a-

CD69+

CD27+

CD4-

CD8+

CD45RO-

CD45RA+

CD4+ CD25++ CTLA-4+

CD45RA-

IL-10IFN-γ(ref. 26) antigen

TGF-β(ref. 27,28)

Flt-3 LigandIL-7IL-15(ref. 7,10,11)

IL-2IL-12

CD58+

CD54+

CD80+

CD86+

MHC-ΙΙ+(ref. 17,18)

IL-7 is suggested to be less critical to B cell development in man than in mouse.76

(CFU-BLAST)Primitive Stem Cell

CD34++

CD38-

CD71- CD33+

CD10-

CD5-

CD90+/Thy-1+

CD45RA-

(ref. 30,46,47,69,70)

G-CSF

Resting

CD34- Stem Cell (in adult)

Proliferation induced by:Flt-3 LigandTpoSCF/c-kit LigandIL-3(ref. 54, 58)

(ref. 66)

(ref. 67,68)

GEMM

CFU-GM

CFU-MASTCFU-G

CFU-M

Dendritic Cell

Macrophage

Neutrophil

CD34+

CD33+

CD13-

MHC-ΙΙ+CD10-

Thy-1/CD90-

CD45RA-

CD38+

(ref. 30,43,44,45,46)

CD34+

CD71+

CD45RA-

SCF R/c-kit+++

CD38+

CD33-

glycophorin-

T200++

MHC-ΙΙ+

CD34++

CD38-

CD7++

CD44++

Notch-1+

CD33+

CD2-

CD5-

CD1a-

CD45RA+

IL-7 Rα+

(ref. 4,6,7)

CD34-

CD4+

CD45RA+

IL-3 Rα+

CD11c-

MHC-ΙΙ+

TLR7+

TLR9+

BDCA-2+

(ref. 16,17,18,19)

CD34+

SCF R/ c-kit+ Tpo R+ MHC-ΙΙ-CD41-

CD45RA-

(ref. 71,72,73)

CD33++↓ CD45RA- CD11b+ CD54+/-↓ CD66++ CD24+

CD2+

CD11b+

CD14+++

CD33+

CD40-

CD80-

CD86-

(ref. 42)

CD10+

CD11b+ CD24+

CD33+↓ CD45RA- CD54+/- CD66++

CD33++ CD45RA++ CD13+ CD24- CD10- CD11b-

CD66-

CD54++

(ref. 44,52)

CD14-

CD86+

CD40+

CD1a+

CD9+

CD68+

MHC-ΙΙ+CD38+

(ref. 16)

CD2-

CD11b+

CD14+++

CD33+

CD40-

CD80-

CD86-

CD45RA-

TRL2+

TRL4+

TRL5+

TRL8+

(ref. 16,17,42)

CD34+ CD33++ CD38+ SCF R/ c-kit+/- CD45RA+ CD10- CD54++ CD13+

(ref. 43,44,52,53)

SCF R/ c-Kitlo

CD13+

CD45RA+

CD33+

MHC-ΙΙ+CD2+/-

CD7+/-

CD34-

(ref. 43,44,54)

CD1a+ CD80+ CD32+ CD54+ CD11c+ MHC-ΙΙ+ (ref. 21,22)

CD34-

FcεRI+SCF R/c-kit-

MHC-ΙΙ-Trypase+

Chymase+

(ref. 50,51)

SCF/c-kit LigandIL-3IL-9Epo(ref. 55,57,80)

SCF/c-kit LigandIL-3IL-9Epo(ref. 55,57,80)

IL-3IL-11(ref. 71)

IL-3IL-11(ref. 71)

GM-CSFIL-3SCF/c-kit LigandFlt-3 Ligand(ref. 55,57)

GM-CSFIL-3SCF/c-kit LigandFlt-3 Ligand(ref. 55,57)

IL-3SCF/c-kit Ligand

(ref. 48)GM-CSFIL-3SCF/c-kit Ligand(ref. 55)

GM-CSFIL-3SCF/c-kit Ligand(ref. 55)

M-CSF (ref. 54,55)M-CSF (ref. 54,55)

M-CSF M-CSF

M-CSF

G-CSF IL-3 (ref. 55,56)

G-CSF IL-3 (ref. 55,56)

IL-4GM-CSF(ref. 64,65)

IL-5(ref. 48)

CD40LTNF-α

G-CSF (ref. 55,56)G-CSF (ref. 55,56)

TpoIL-6(ref. 62)

TpoIL-11(ref. 75)

TpoIL-11(ref. 75)

IL-3GMCSFTpoIL-6(ref. 63,71)

*CFU-E’s are almost indistinguishable from BFU-E (ref. 60). CFU-E are reported to show a slight reduction in MHC-ΙΙ (ref. 60) and a slight increase in CD71 (ref. 59).

CFU-E

Pronormoblast

Megakaryocyte

Reticulocyte

GM-CSFEpo (ref. 55)

T200+

CD71++

glycophorin++

(ref. 59)

EpoIL-3(ref. 55)

EpoIL-3(ref. 55)

CD71-

glycophorin++

T200+/-

(ref. 59)

Platelets

CD41lo

CD61+

CD34+

MHC-ΙΙ+Tpo R+

CD45RA-

CD42-

CD32-

(ref. 54,61,71,72,73,74)

Tpo R+

CD34-

CD41+

CD42+

CD32+

MHC-ΙΙ-(ref. 71, 73)

FGF-2(ref. 25)

Neutrophilic Myelocyte

IL-3 (ref. 56)

Monocyte / Pre DC1

Immature DC1

Mature DC1

(Immature?)MAST CELL (MCT)

MAST CELL (MCTc)

CD34+

CD13+

SCF R/c-kit+

FcεRI-CD33+

MHC-ΙΙ+CD38+

Trypase-

Chymase-

(ref. 48,50)

CD34-

CD13+

SCF R/c-kit+

FcεRI-CD33+

CD38+

MHC-ΙΙ-Trypase+

Chymase-

(ref. 48,50,51)

Multipotential Thymic Precursor

Thymic DC

T / NK ProgenitorT / NK Precursor

Pre-NK Cell

Immature NK Cell

Mature NK Cell

LAK Cell

Flt-3 LigandFlt-3

Ligand

Flt-3 Ligand

CD40LIL-3

Pro-DC2

Pre-DC2

Immature DC2IFN-α/β+++

virus (ref. 20)

IL-12IL-18

(ref. 12,13)

IL-2(ref. 14)IL-2(ref. 14)

IL-4(ref. 15)IL-4(ref. 15)

IL-12

NK2 Cell

NK1 Cell

90% of Blood NK Cells

10% of Blood NK Cells

IFN-γ

Pre-T1

Pre-T2 / CD4+ Immature

Early Double-positive Thymocyte

Late Double-positive Thymocyte

IL-7

IL-7

γδ T cells

Endstage Cell

Functional CD8+ T Cell

Functional CD4+ T Cell

Th1

Th2

Tr1

Th3 Cell

Th2

Th1

or CD4+

(CD25+ ??)IL-10 & IFN-γ

IL-12, IL-27

IL-4

IFN-γ,

IL-12

, IL-18, IL-23

B7ICOS-LIL-4

Immunosuppression by regulatory T cells is suggested to involve cell-to-cell contact. In mice, CD25+ regulatory T cells are reported to have cell surface TGF-β, which may mediate this e�ect (ref. 29).

TGF-β(ref. 24)

TGF-β(ref. 24)

TGF-β(ref. 24)

BFU-E

BFU-MK

CFU-MK

SCF/c-kit LigandIL-6

(ref. 49,50)

IL-4

To the Liver

IL-12

GM-CSFEpo (ref. 55)

CD34-CD34- CD43+ CD10+↓

CD45RA++↑ TdT- IL-7 Rα-

H e m a t o p o i e s i s D e v e l o p m e n t

c y t o k i n e s i n c y t o k i n e s i n

R&D Systems, Inc., 1-800-343-7475, www.RnDSystems.comPM103_hematopoiesis_APR

NOTE: This poster conveys a general overview of selected aspects of hematopoietic cell development and should be considered neither comprehensive nor definitive. The details of the process are understood to be subject to interpretation. For a complete list of references, please refer to www.RnDSystems.com/go/PosterRefs © R&D Systems, Inc. 2003