Response in infants Polyclonal activation B Cell types B cell responses to antigens In xid mice (BTK-) Antigen types B Cell Antigen Receptor TI-2TI-1 Mature.

Response in infants

Polyclonal activation

B Cell types

B cell responses to antigens

In xid mice (BTK-)

Antigen types

B Cell Antigen Receptor

TI-2TI-1

MatureB cells

in general

B1 cells,marginal

zone B cells

Yes No

Yes No

NoYes

Bacterial cell wall

components

Highly repetitive structures

Indep. Dep.

T cell-independent

FollicularB cells

No

Yes

Yes

Proteins, CHO, lipids

Dep.

T cell-dependent

TI-1 antigens

- many are bacterial cell wall products, such as LPS,peptidoglycan, lipoprotein, porin

- many are recognized by Toll-like receptors

- potent but non-specific inducer of B cell proliferation

TI-2 antigens

- present on encapsulated bacteria and some viruses

- repetitive epitopes with regular spacing

- epitopes expressed on a rigid molecular backbone

- induce B cell response by cross-linking B cell antigen receptors

TLR

CR2

Modulation of TI-2 responses - second signals for activation

IL-2, IFN-,IL-3, GMCSF, IL5

T cells,NK cells

IC

(cognate recognition?)

TI-1 antigen(same or diff.Microbe)

TACI

BLys, APRIL

(1) B1 cells:

- Localized to the peritoneal and plueral cavities

- Their repertoire is skewed toward reactivity with TI-2 antigens;

- the inability of xid mice to respond to TI-2 antigens could be

due to the lack of B1 cells in these mice

- TI-2 activation of B cells, but not TD or TI-1, in vitro

results in a partial induction of the B1 phenotype

(2) marginal zone (MZ) B cells

- Localized to the perimeter of splenic white pulps

- Unlike follicular B cells, MZ B cells are not circulating

- with high levels of cell surface complement receptor 2 (CD21)

B cells reponsive to TI-2 antigens

TI response to particulate antigen,

(PC) Phosphorylcholine+ S. pneumoniae

MZ B1 B1

Spleen Peritoneal cavity

Plasmablasts Plasmablasts

bacteria bacteria

Question:

How are PC+ MZ B cells activated?

Study: Balazs et al, 2002. Immunity 17: 341-352

MZ B moves to DC

But not to M or neutrophils

C56BL/6 T-deficient

MZ B and DC with bacteriaPre-immune

Fig. 1 PC-specific MZ B migrates to DC after immunization

Conclusion of Fig. 1 - MZ B cells in close contact withdendritic cells containing bacteria

Experiments further showed:(1) the major cell type that capture bacteria from the blood is CD11clo dendritic cell

(2) CD11clo dendritic cells move from the blood to the spleen rapidly after immunization, and “present” the bacteria to the antigen-specific MZ B cells

(3) soluble factors, Blys and/or APRIL, derived from the CD11clo dendritic cells support the survival of these antigen-specific B cells; and is important for the full differentiation of the MZ B cells to plasmablasts

Fig. 3

Blood DC (CD11clo)or neutrophils that have phagocytosedbacteria migrate to spleen

Fig. 5 - Binding of soluble ligand to TACI is responsible for plasmablast differentiation of PC+ MZ B cells (in vitro)

Fig. 6

Binding of ligand to TACI is responsible for plasmablast differentiation of PC+ MZ B cells (in vivo)

1st division

2nd division

CMFDA assay for cell division

Fig. 7

Binding of ligand to TACI is responsible for survival of PC+ MZ B cells

TACI ligands

Activation of MZ B cells

Plasmablasts

Survival & differentiation

PC+ MZ B cells

TACI

PC+ MZ B cells

CD11clo blood DCmigrate to spleen aftercapture of bacteria

Fig.2

In vitro primedBMDC and PEC Mpromote plasmablast differentiation from PC+MZ B cells

Bacteria-primedblood DCpromote plasmablast differentiation fromPC+ MZ B cells

Fig. 4