T cell differentiation, migration Institute for Research ......Institute for Research in Biomedicine...

Institute for Research in Biomedicine

T cell differentiation, migration

and immune regulation

Antonio Lanzavecchia


Bellinzona, Switzerland

[email protected]

J-L Casanova

Increased life expectancy and medical progress

Naïve T cellsLow frequency

Homogeneous

Resting “spores”

Poorly responsive

Memory T cellsHigher frequency

Heterogeneous

Slowly dividing

Highly responsive

From naïve to memory T cells

Effector T cellsUp to >50% of circulating T cells

Immediate effector function

Short lived

ImmatureDC

Cell migration in the immune response

Naïve T & B cells

B

Peripheral tissue

Lymph node

Blood

T

Effector phase

Th1, Th2, CTLPC

Antibodies

Mature

DC

Pathogen

Dendritic cell maturation in vitro

Antigen capture1 Macropinocytosis ++ + -

Mannose R ++ + -

Antigen MHC II synthesis + ++ -

presentation2 MHC II halflife 10 h >100 hMHC I synthesis + ++ ++

Migration4 CCR5 + (+) -CCR7 - + ++

Cytokines5 TNF IL-6 IL-1 - + -

IFN-I - + -IL-12 - +/- -

monocyte immature DC

GM-CSF + IL-4

Maturation Maturation Maturation Maturation stimulistimulistimulistimuli

“exhausted”“active”

Costimulation1 B7 - + +

1) Sallusto et al JEM 1994; JEM 1995; 2) Cella et al Nature 1997; 3) Cella et al JEM 1999; 4) Sallusto et al EJI 1998; 5) Langenkamp et al Nat Immunol 2000

24 h

DC activation: integration of multiple stimuli

PAMPS �� PRRLPS, CpG… �� TLRs

dsRNA �� RIG-I, MDA5

MDP �� NOD2

CytokinesTNF IL-1

IFN-αααα/ββββ (pDC/IPC)

IFN-γγγγ (NK cells)

TSLP

DAMPSUrates, ATP, alum

��NALP3

T helper cellsCD40L �� CD40

DC maturation

(~6000 genes)

1. Migration

2. Antigen presentation

3. Costimulation

4. Cytokines (IL-12, IL-23,

IL-1, IL-6, IL-27…)

IL-12p70 production is triggered by synergic TLR stimulation

and is further boosted by CD40L

0.1

1

10

100

1000

IC +

R848

LPS +

R848

IC R848 LPS-

IL-1

2p7

0 (

ng/m

l)

medium

CD40L

2 µg/106 cells

1. T cell activation and fate determination

2. Human effector/memory T cell subsets

(TCM, TEM, Th1, Th2, Th17, etc)

3. T cell traffic in steady state and inflammatory

conditions (mouse)

“Signal strength”

Polarizing cytokines

T cell fate

Dendritic cell

Inte

nsity

time

Signal = I x t

T cell fate

4. [Polarizing cytokines] Differentiation

IL-12

IL-4

3. Stability of the synapse Duration of signalling

DC

Tproliferation

differentiation

death

2. [B7] Amplification

Raft

CD28

B7

LcK, LAT

1. [peptide-MHC] Rate of TCR triggering

TCR

P-MHC

Signal strength and activation thresholds

Iezzi et al, Immunity 1998

Iezzi et al, JEM 2000

Langenkamp et al, Nat Immunol 2000

Langenkamp et al, EJI 2002

Gett et al, Nat Immunol 2003

Messi et al, Nat Immunol 2003

The strength of stimulation determines T cell fate

T naive

AICD

IL7/IL15R+

CCR7+ CD62L+

Non effector

“Fit” Migrate to secondary lymphoid organs

Migrate to inflamed tissuesIL7/IL15R+

CCR7- CD62L-

Effector

“Unfit” Die by neglectIL7/IL15R-, BCL-XL–

DC

Strength / duration of stimulation

DC maturation and density, antigen concentration,

stochastic T-DC interactions and T-T competition

Polarizing cytokines





conditions (mouse)

Central memory

CCR7+Effector memory

CCR7−

Th1

Th2

Th17

TNP

Treg

pre-Th1

TFH

Central

memory

Effector

• Strength / duration of stimulation

• T-DC serial encounters

• Polarizing cytokines

• Asymmetric division

• Migratory capacity

• Effector function

• Differentiation potential

• Survival

Dynamics of T lymphocyte responses:

intermediates, effectors and memory cells

T cell areas of secondary lymphoid organs

Non-polarized

IL-2

CCR5

CXCR3

CCR3

CCR4

CRTh2

Peripheral tissues

Th1 Th2 CTL

Effector memory

Central memory

CCR7+

CD62L+

CCR5

CXCR3

CXCR6

perforinIFN-γ IL-4

Blood

Two subsets of memory T cells with distinct Two subsets of memory T cells with distinct Two subsets of memory T cells with distinct Two subsets of memory T cells with distinct migratory capacity and effector functionmigratory capacity and effector functionmigratory capacity and effector functionmigratory capacity and effector function

Sallusto et al. Nature 401: 708 (1999)

b

a

Naïve T

Effector memory T

T cell clonal dynamics: primary responses

c

o

z

wm

u

p s

q g

Central memory T

Ag-X

Dendritic cells

xx

xx

x

x

o

z

wm

u

p s

x g

s

x

xx

x

x

x Short lived

effector T cells

xx

x

b

a

Naïve T

Effector memory T

c

o

z

wm

u

p s

q g

Central memory T

o

z

wm

u

p s

x g

s

x

Secondary response Immediate protection

Central and effector memory T cells are stable years

T cell clonal dynamics: memory phase

Tracking T cell division by CFSE dilution (Lyons & Parish)

CFSE

CFSE

labeling

Stimulation

Proliferation

Stability of central memory and effector memory T cells

DBO

DJA

Donor

Naïve TEffector

memory T

Central

Memory T

Rivino et al, J Exp Med 2004

CFSE

Time after

TT boost

6 months

12 years

CFSE-labeled T cells stimulated by antigen-loaded autologous monocytes

TT

CCR4+CXCR3+TN TEM CXCR5+

TCM

CFSE

CMV

VV

Antigen-specific T cells are differentially distributed

in memory subsets

Rivino et al, J Exp Med 2004

Division of labor among memory T cells

Central memory T (TCM)

TCM circulate through secondary

lymphoid tissues

Secrete IL-2 but little IFN-γγγγ and no

perforin

Robust proliferation capacity and

transition into effector cells that can

migrate to non-lymphoid tissue

Differentiation intermediates

Effector memory T (TCM)

TEM circulate through and can reside

in non-lymphoid tissue

Secrete IFN- γγγγ and perforin but little

IL-2

Limited proliferation capacity but

display of immediate effector

function

Terminally differentiated

Secondary responses Immediate protection

The Th1 / Th2 paradigm

Th1

naïve

CD4 T

Microbial products

Adjuvants

DC

IFN-γγγγ, IL-12 / T-bet

Intracellular bacteria,

Viruses

Parasites

Allergy

IL-4, IL-5, IL13

CCR3+ CCR4+ CRTh2+

Th2

IFN-γγγγ

CXCR3+

IL-4 / Gata-3

Plasticity of cytokine gene expression in TEM

Cytokineproduction

IFN-γγγγ

IL-4

IL-4+IFN-γγγγ

CCR7

-

-

-

Openchromatin

ifng

il4

Ifng and il4

TH1

TH2

TH0

TEM

CRTh2

Ag

IL-12

Subset specific, loss of T-bet

Some

TEMAg

TEMAg

IL-4

TEMAg

IL-12

Most

Messi et al, Nat Immunol 2003

Chromatin configuration:

Th17: a novel subset of CD4 effector T cells

Th1

naïve

CD4 T

Microbial products

Adjuvants

DC

Th17

IFN-γγγγ, IL-12 / T-bet

IL-4 / Gata-3

IL-6, IL-1, TGFββββ

IL-23 / RORγγγγt

Intracellular bacteria,

Viruses

Parasites

Allergy

Autoimmunity

Extracellular bacteria?

IL-4, IL-5, IL13

Th2

IFN-γγγγ

IL-17, IL-22, TNF

Can we identify Th17 cells using surface markers?

Which are the pathogens that trigger Th17 responses?

Human memory T cells

(CD4+ CD45RA– CD25–)

CCR6-positiveCCR6-negative

Acosta-Rodriguez et al, Nat Immunol, 2007; Reboldi et al, Nat Immunol, 2009

IL-17 production is characteristic of a CCR6+ subset

Mouse memory T cells

(CD4+ CD25– CD44hi)

IL-1

7

IFN-γ

CCR6-positiveCCR6-negative

IL-1

7

IFN-γ

Ex-vivo from blood Ex-vivo from spleen

Human Th17 memory cells co-express

CCR6 and CCR4 and express RORγγγγt

Th1Th17 Th1* Th2

RO

Rγγ γγt

mR

NA

(A

U)

0

10

20

30

40

0

10

20

30

40

0

10

20

30

40

0

10

20

30

40

n.d n.d n.d n.d

Ex vivo

In vitro stimulation

2 0.2

14.8

83

0 0.7

93.35.9

49.6 7.1

5.338

CCR6+ CCR6-

CCR4+

2.1 33.5

62.52

CCR4+ CXCR3+ CXCR3+

IL-1

7

IFN-γγγγ

Th17

CCR6+

CCR4+

Th1*

CCR6+

CXCR3+

CCR6-

C. albicans M. tuberculosis PPD

CD

3

CFSE

IL-17

IFN-γγγγ

ng

/ml

CCR6+

CCR4+

CCR6+

CXCR3+

CCR6-

C. albicans

0.01

0.1

1

10

CCR6+

CCR4+

CCR6+

CXCR3+

CCR6-

M. tuberculosis PPD

0.01

0.1

1

10

ng

/ml

C. albicans specific memory cells are Th17

0.0

0.4

0.8

1.2

1.6

2.0

ng/m

l

IFN-γIL-17

Yeast Hyphae

C. albicans

Priming naïve CD4+ T cells

0.0

0.2

0.4

0.6

0.8

1.0

ng//

ml

107106105104

C. albicans Yeast C. albicans Hyphae

0.0

0.2

0.4

0.6

0.8

106105104103

1.0

ng//

ml

IL-12

IL-23

IL-12 and IL-23 production by DC

C. albicans hyphae selectively induce IL-23

and prime Th17 cells

• Th17 memory cells express CCR6 and CCR4

• C. albicans specific memory cells are Th17

• The Hyphal form of C. albicans triggers IL-23, but not IL-12

• Th17 deficiency and candidiasis in STAT3 deficient patients (Milner et al Nature 2008; Ma et al JEM 2008)

Th17 cells might recruit neutrophils thus promoting

entrapment and killing of hyphae

Th17 and immunity to fungi

Th22: a new subset of T helper cells?

Thomas Duhen


… but most IL-22-producing cells do not produce IL-17

CC

R6-

CC

R6+

CC

R6-

CC

R6+

IL-2

2 p

rod

ucin

g T

cell

s (

%) 20

15

10

5

0 0

0.5

1

1.5

IL-2

2 (

ng

/ml)

0.6 0.5

24.9

13 5.8

29.7

14.4 4.4

4.1

1.09 0.1

0.1

IFN-γ

IL-2

2

CCR6− CCR6+

IL-2

2

IL-17

CD4+ CD45RA−−−− CD25−−−− T cells

(ex vivo stimulation)

IL-22-producing T cells are present in the

CD4+ CCR6+ memory subset

Skin-homing T cells (CCR4+ CCR10+ CLA+)

produce IL-22, but no IL-17

Th22 clones do not express ROR-c

Th22 clones Th17 clones

How are IL-22-only producing CD4+ T cells generated?

Plasmacytoid DC prime IL-22-producing T cells

100 101 102 103 104100 101 102 103 104100 101 102 103 104

68.6

cDC

100 101 102 103 104100 101 102 103 104100 101 102 103 104

62.8

pDC15.9 37.50.1 0.1

23.653.1

2.0 6.40.1 0.1

43.88.3

Cytokine production

following PMA + ionomycin

IL-22 IL-17

IFN-γIL-22

CD4+ naïve T cells

primed by allogeneic:

CFSE

IL-22

IFN-γIL-22

IL-17

IL-6 and TNF produced by pDC are required

for Th22 polarization

Mean of 5 donors

1500

1000

500

0

med

ium

CpG

200

6

R-8

48

cyto

kin

e p

rodu

ction (

pg/m

l)

IL-6

TNF-α

IL-2

2 o

nly

pro

ducin

g T

cells

(%

)

100

80

60

40

20

0

anti-

IL-6

Ran

ti-TN

F

anti-

IL-6

R +

ant

i-TN

F-

pDC + CpG 2006

Vitamin D3 and pDC promote expression

of CCR6 and CCR10

TH22 IL-22 KeratinocytesCCR6 / CCR10 ??

TH1

TH2

TH17

IFN-γ

IL-4, IL-5, IL-13

IL-17, IL-22

Macrophages

Eosinophils

Neutrophils

Bacteria

Parasites

Fungi

T-bet

GATA-3

ROR-γt

CXCR3

CCR4/CRTh2

CCR6 / CCR4

TFHIL-21 B cells AntibodiesBcl-6 CXCR5

Treg TGF-β DC / T cells RegulationFOXP3 CCR7 / CCR6

Tr1 IL-10 T cells Regulation? CCR7 / CCR6

IL-6, TNF

IL-12. IFN

IL-4

IL-6,IL-1β.TGF-β

IL-21

?

IL-10

FunctionModulePolarizing

cytokine(s)

Transcription

factor

Homing

receptor(s)

Effector

cytokine(s)

Target

cell

Th22: a module of adaptive immunity dedicated

to epithelial cell physiology?

Human T cell repertoire analysis using amplified

T cell libraries

Rebekka Geiger


Challenges in analyzing the

human naïve T cell repertoire

• Low frequency of antigen-specific naïve T cells

• High activation threshold of naïve T cells

• Broad spectrum of avidities

• Limitations of peptide-based and tetramer-based

approaches

• Need to measure T cell responses to complex

naturally processed antigens

KLH, Anthrax…

(primary antigens)

TT, CMV, PPD…

(recall antigens)

Thyroglobulin…

(self antigens)

2nd step: Interrogation

Each culture is tested

for proliferation in response

to Ag and autologous APC

Analysis of naïve and memory T cell repertoires

using amplified T cell libraries

1 naïve T cell �� 5,000 T cell blasts

1st step: Amplification

Multiple cultures (96 up to 384)

each containing 1000 cells

are expanded with PHA and IL-2

Geiger et al JEM 2009

Antigen-specific CD4+ T cells in the

human naïve repertoire

Frequency of KLH-specific naïve T cells

Broad range of responsiveness

Broad range of epitope specificities

Isolation of Ag-specific T cell clones

from the naïve repertoire

Analysis of memory repertoires

Increased frequencies in the memory

compartment (Tet Tox)


compartment (CMV)

Selection of high avidity T cells

in the memory pool

Applications

• Predict antigenicity of complex molecules

(even whole pathogens)

• Assess immunocompetence (elderly, HIV)

• Assess memory in different T cell subsets

• Generate T cells for cellular immunotherapy





conditions (mouse)

TEM and NK(CCR7-, CD62L-)

Paradigm: migration from blood to lymph nodes requires CCR7 and CD62L

Resting

lymph node

Blood

Tissue

iDC

TNaive and TCM

(CCR7+, CD62L+)

NK(CCR7-)

NK cells migrate to reactive lymph nodes in a CXCR3-dependent fashion

Resting

lymph node

Blood

Tissue

iDC

TNaive and TCM

(CCR7+, CD62L+)

reactive

lymph node

mDC

Microbial products

TNF

Martin-Fontecha et al Nat Immunol 2004

NK cells produce IFN-γγγγ

that is required for Th1

polarization

IFN-γ

NK (CXCR3)

CD8+ TEM / CTL(CCR7-, CD62L-)

Blood

Tissue

iDC

TN and TCM

(CCR7+, CD62L+)

mDC

Guarda et al Nat Immunol 2007

CD8+ effector cells kill

antigen presenting DC

Effector and effector memory CD8 T cells migrate to inflamed lymph nodes

in a CXCR3 dependent fashion and kill antigen presenting dendritic cells

CD8+ TEM / CTL (CXCR3)

Resting

lymph nodereactive

lymph node

Microbial products

TNF

Blood

Tissue

OVA-CD4+ TEM

CD62P

Effector memory CD4 T cells license DC in chronically inflamed lymph nodes

CD4+ effector memory T cells

• migrate to chronically reactive lymph

nodes via CD62P

• Constitutively express CD40L

• Trigger DC maturation

Blood

Tissue

Autoreactive

T cell priming

�� EAE

OVA-CD4+ TEM

MOG

CD4+ effector memory T cells

• migrate to chronically reactive lymph

nodes via CD62P

• Constitutively express CD40L

• Trigger DC maturation

• Cause EAE in the absence of adjuvantCD62P

Effector memory CD4 T cells license DC in chronically inflamed lymph nodes

Induction of EAE by MOG in PBS draining to a chronic lymph node

MOG in PBS / Resting LN

0

1

2

3

4

Clin

ical S

core

9 13 17 25 29 33211 5

27.4

28.1

Clin

ical S

core

0

1

2

3

4

9 13 17 25 29 33211 5

0

0

1

2

3

4

Clin

ical S

core

1 5 9 13 17 25 29 3321

20.1

0

0

1

2

3

4

Clin

ical S

core

9 13 17 25 29 33211 5

19.9

0

Days

MOG in PBS / Chronic LN (CFA)

+ anti-CD62P

+ anti-CD62P+ / - anti-CD62P

Days

MOG in CFA / Resting LN MOG in PBS / Chronic LN (2X DC)

The role of CCR6 in experimental autoimmune

encephalomyelitis

Andrea Reboldi

CCR6-KO mice (Cook et al, Immunity 2000)


Pathogenesis of Multiple Sclerosis

Ransohoff et al

CCR6-KO mice do not develop EAE

Green, CD45

Red, laminin

Immunoperoxidase staining, CD45

Hemalaun counterstain

WT

CCR6-KO

WT

CCR6-KO

MOG35-55 in CFA (s.c.) + PT

In CCR6-KO mice MOG-reactive Th17 and Th1

cells are primed but do not migrate into the CNS

Cytokine production following restimulation with MOG peptide:

IL-17 IFN-γ

WT naive

2D2 T cellsi.v.

MOG+CFACCR6-KO

Transfer of wild-type 2D2 T cells reconstitutes

disease susceptibility in CCR6-KO mice

… but on day 20 the T cells in the CNS

are endogenous CCR6-/- Th1 and Th17

CCR6-KO mice transferred with CCR6+/+ GFP+ 2D2 T cells (Day 20)

IL-17 IFN-γγγγ

– 2D2

CCR6-KOWT

– 2D2– 2D2

CCR6-KOWT

– 2D2

Spleen

71.3 0.08

Brain

CD

4

GFP

84.6 0

Cytokine production following

restimulation with MOG peptide:

CCR6 is not required for rolling and adhesion to

inflamed endothelial cells of CNS parenchyma

Firmly adherent CCR6-KO T cells

10min after injection

in score 2 EAE mice

X20

∅30µm

activated

T cells

∅20µm

Intravital microscopy

In EAE, effector T cells generated upon immunization

have to enter a normal non inflamed brain.

Initial entry of CCR6+ T cells by a constitutive pathway

may be required to trigger subsequent recruitment of

effector T cells by an inflammatory pathway through

activated endothelial cells of the blood brain barrier.

CCR6+ T cells as gate keepers for entry

in an intact CNS?

CCR6 requirement under steady state conditions

and at early time points during EAE

Brain Spleen

Migration of WT and CCR6-KO T cells

WT T cells

CCR6-KO T cells

Brain CD4+ T cells in

steady state conditions

WT CCR6-KO

Which is the initial port of entry of CCR6+ T cells?

Modified from Ransohoff et al, Nat Rev Immunol 2003

Routes for leukocyte migration into the CNS

Subarachnoid space

Choroid plexus

Pial membrane

Dural membrane

Arachnoid membrane

Parenchymal vessels

Meningeal vessels

BBB

BCSFB

Is the choroid plexus the port of entry

of CCR6+ Th17 cells?

Engelhardt and Ransohoff, Trends Immunol 2005

CD45 Ab

Wild-type CCR6-KO

In CCR6-KO mice immunized with MOG+CFA

lymphocytes are trapped in the choroid plexus

CD45 Ab

The CCR6 ligand CCL20 is highly expressed

in epithelial cells of the mouse choroid plexus

CCL20 Ab

Wild-type CCR6-KO

The CCR6 ligand CCL20 (LARC) is constitutively

expressed in human choroid epithelium

Constitutive and inflammatory routes of entry into the CNS:

a two step model of EAE pathogenesis

(1) CCR6-mediated Th17 cell entry

into the CSF via choroid plexus

(2) Th17 dissemination via the CSF

to the subarachnoid space

(3) Antigen recognition and

local activation of the BBB

(4) CCR6-independent T cell entry through

locally activated parenchimal venules of BBB

• How do CCR6+ T cells trigger leukocyte recruitment?

• Which are the chemokine receptors involved in late EAE?

• What is the relative contribution of Th17 and Th1 cells

at different stages of the disease?

• Does CCR6-blockade have any therapeutic effect (relapsing-

remitting SJL model)?

• Do CCR6+ T cells play a role in surveillance of the CNS?

CCR6+ T cells as gate keepers for CNS entry

Human T cell repertoire analysis using amplified

T cell libraries

Rebekka Geiger


Challenges in analyzing the

human naïve T cell repertoire

• Low frequency of antigen-specific naïve T cells

• High activation threshold of naïve T cells

• Broad spectrum of avidities

• Limitations of peptide-based and tetramer-based

approaches

• Need to measure T cell responses to complex

naturally processed antigens

KLH, Anthrax…

(primary antigens)

TT, CMV, PPD…

(recall antigens)

Thyroglobulin…

(self antigens)

2nd step: Interrogation

Each culture is tested

for proliferation in response

to Ag and autologous APC

Analysis of naïve and memory T cell repertoires

using amplified T cell libraries

1 naïve T cell �� 5,000 T cell blasts

1st step: Amplification

Multiple cultures (96 up to 384)

each containing 1000 cells

are expanded with PHA and IL-2

Geiger et al JEM 2009

Antigen-specific CD4+ T cells in the

human naïve repertoire

Frequency of KLH-specific naïve T cells

Broad range of responsiveness

Broad range of epitope specificities

Isolation of Ag-specific T cell clones

from the naïve repertoire

Analysis of memory repertoires


compartment (Tet Tox)


compartment (CMV)

Selection of high avidity T cells

in the memory pool

Applications

• Predict antigenicity of complex molecules

(even whole pathogens)

• Assess immunocompetence (elderly, HIV)

• Assess memory in different T cell subsets

• Generate T cells for cellular immunotherapy

The Lanzavecchia & Sallusto Lab

Giorgio Napolitani (Th17)

Andrea Reboldi (EAE)

Thomas Duhen (Th22)

Rebekka Geiger (T cell libraries)

Martina Beltramello (dengue)

Davide Corti (influenza)

David Jarrossay (plasma cells)

Dirk Baumjohann

Annalisa Macagno

Janine Stubbs

Debora Pinna

Blanca Fernandez

Chiara Silacci

Fabrizia Vanzetta

Eva Acosta-Rodriguez, Cordoba - Jens Geginat, Berlin -

Mara Messi, Basel - Amanda Gett, Basel - Laura Rivino,

Berlin


C

N

NC

H3 H1

H2L2

L1L3

V L

H2C

H1C

V H

H3C

V L

V H

H1C

H2C

H3C

C LC L

AntibodyAntibodyAntibodyAntibody

Antigen binding siteAntigen binding siteAntigen binding siteAntigen binding site

SS

Multispecificity / Crossreactivity / Promiscuity / Degeneracy

BostromBostrom et al Science 2009et al Science 2009

Antiviral activities of antibodies

affinity / avidity / accessibility

Antiviral activities of antibodies

“Central memory”

“Effector memory”

Memory B cells

Central memory T cells

Plasma cells (Ab)

Effector memory T cells

• Differentiation intermediates

• In secondary lymphoid organs

• Recall responses

• Fully differentiated

• In peripheral tissues

• Immediate protection

The cellular basis of immunological memoryThe cellular basis of immunological memoryThe cellular basis of immunological memoryThe cellular basis of immunological memory

b

a

Naïve B

o

z

wm

u

p s

x g

Bone marrow

long lived

plasma cells

B cell clonal dynamics: primary responses

c

o

z

wm

u

p s

q g

Memory B

Serum antibodies

IgG1 halflife 3 weeks

Ag-X

Th cells

x xx

xx

x

x

s

x

xx

x

x

x

Short lived

plasma cells

GC reaction

Switch,

Mutations

Radbruch et al Nat Rev Immunol, 2006

Bone marrow niches for long lived plasma cells

b

a

Naïve B

o

z

wm

u

p s

x g

Bone marrow

long lived

plasma cells

B cell clonal dynamics: sustained serum antibodiesB cell clonal dynamics: sustained serum antibodies

c

o

z

wm

u

p s

q g

Memory B

Serum antibodies


s

x

Serum antibodies to vaccinia virus are maintained constant for a lifetime

b

a

Naïve B

o

z

wm

u

p s

x g

Bone marrow

long lived

plasma cells

B cell clonal dynamics: secondary responses

c

o

z

wm

u

p s

q g

Memory B

Serum antibodies


Antigen x

Th cellsx x

xx

x

x

x

s

x

xx

x

x

x

Short lived

plasma cells

“Original antigenic sin”

Kinetics of circulating plasma cells,

memory B cells and serum antibodiesA

nti

-TT

Ig

G (µµ µµ

g/m

l)

0.1

1

10

100

0 100 200 300 400 500 600 700

Time (days)TT TT

Time (days)

Pla

sm

a c

ell

s /

10

6P

BM

C

0.1

1

10

100

1000

10000

0 2 4 6 8 10 12 14 16 18 20 22 24

TT specific IgG

ASC

Total IgG ASC

TT

Ag-specific IgG+ B cells (‰)

on day 14

Human memory B cell subsetsHuman memory B cell subsets

CD27

IgA

+Ig

G

IgM memory /

Marginal zone B cells

Naïve B

CD19+ cells

Switch memory B

T cell differentiation, migration Institute for Research ......Institute for Research in Biomedicine...

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