in vivo

Role of TLR-MyD88 signals for B cell
recruitment, activation and class switch
recombination in Peyer’s patch germinal
centers.
Germinal centers (GCs) are recognized as
the main sites for generation of IgA in the Peyer’s
patch (PP), yet the mechanisms that control B
cell recruitment, activation, and IgA production
in GCs are not completely understood.
We found that bacterial stimulation through
TLR-MyD88 regulates follicular maturation
and GC reaction in the gut immune system.
Unexpectedly, we found that TLR-stimulation of
Figure 1. Proposed model for CP and ILF formation
and generation of IgA in ILFs in the
absence of T cells. (A) The formation of
CPs requires the presence of RORγt + LTi
cells and their interaction with SCs
through LTβR and NIK. This interaction
leads to activation of SCs and production
of adhesion molecules and chemokines,
which are involved mainly in the
recruitment of DCs. CPs receive signals
from gut bacteria, most likely through the
DCs. Concomitant signals from RORγt + LTi
cells through LTβR and bacteria through
TLRs further augment the activation
of SCs, leading to recruitment of B
cells and organization of ILF. (B) The
recruited B cells are then activated by
antigen presenting DCs or by polyclonal
stimulation by the captured microbes.
Activated B cells up-regulate AID and
undergo class switching to IgA, even in
the absence of T cells. TNFα secreted by
both Lin-RORγt + cells as well as activated
DCs induces production of matrix
metalloproteinases (MMPs) that activate
latent TGFβ, leading to preferential class
switching to IgA in the gut. APRIL, BAFF,
IL6, and IL10 produced by SCs or DCs
further enhances the survival of IgA + B
cells and their differentiation into IgA
plasmablasts/plasma cells.
both the BM-derived compartment (B cells and
DCs) and the stromal cell compartment (follicular
dendritic cells FDC) is required for induction
and maintenance of GCs in PPs. Stimulation of
FDCs through the TLR-MyD88 pathway partly
regulated PP GCs formation by recruitment
of B cells and activated helper T cells to the
PP follicles through enhanced secretion of the
specific B cell attractant chemokine CXCL13.
We further demonstrated that PP FDCs support
preferential switching of activated B cells to
IgA through abundant production of TGFβ
(Figure 2).
Recent publications
Tsuji M, Suzuki K, Kinoshita K.,
Fagarasan S. Dynamic interactions
between bacteria and immune
cells leading to intestinal IgA
synthesis. Semin Immunol. 2008
in press.
Ha SA, Tsuji M, Suzuki K, Meek
B, Yasuda N, Kaisho T, Fagarasan
S. Regulation of B1 cell migration
by signals through Toll-like
receptors. J Exp Med. 2006 Oct
30;203(11):2541-50
Suzuki K, Ha SA, Tsuji M,
Fagarasan S. Intestinal IgA
synthesis: A primitive form of
adaptive immunity that regulates
microbial communities in the gut.
Semin Immunol. 2006 Dec 8;
Fagarasan S. Intestinal IgA
synthesis: a primitive form of
adaptive immunity that regulates
microbial communities in the
gut. Curr Top Microbiol Immunol.
2006;308:137-53. Review.
Suzuki K, Meek B, Doi Y, Honjo
T, Fagarasan S.: Two distinctive
pathways for recruitment of naive
and primed IgM+ B cells to the
gut lamina propria Proc Natl
Acad Sci U S A. 2005 Feb 15;102
(7):2482-6.
Figure 2. Role of TLR stimulation of
FDCs in GC formation and
IgA synthesis in the gut.
FDCs located in the light
zone of the PP follicles
express TLRs. They
respond to stimulation
through TLRs by secreting
factors, such as like
CXCL13, that promote
migration and survival
of B cells and CD40L
expressing T cells (Follicular
helper T FH cells). B cell-T
cell interactions through
MHC II-TCR are critical for
the GC reaction in PPs.
Other factors secreted by
FDCs, like TGFβ, facilitate
preferential class switching
of B cells from IgM to IgA.
IgA B cells generated in
GC of PPs migrate to the
lamina propria, where they
further differentiate into
IgA-secreting cells. IgA
transported and secreted
into the intestinal lumen
prevents bacterial access
to the epithelium.
43