Molecular Networks Orchestrating GALT Development

Center for Biomedicine, Developmental Immunology, Department of Clinical and Biological Sciences (DKBW), University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland [email protected]

1 Evolution of Gut-Associated Lymphoid Tissue 20

1.1 Phylogenetic Development of Lymphoid Compartments 20

1.2 Inductive Sites for Mucosal Immune Responses 23

1.2.1 Peyer's Patches 23

1.2.2 Alternative Sites for Immune Responses 25

2 Control of Gut-Associated Fetal Lympho-Organogenesis 26

2.1 Mesenteric LN Formation: From Vasculature to Lymph Sacs 26

2.2 Lymphoid Tissue Inducer Cells 28

2.3 PP Anlage Formation and Mesenchymal Cell Differentiation 29

2.4 Isolated Lymphoid Follicles 31

3 Signaling and Transcription Factors Altering the Development of Secondary Lymphoid Organs 32

3.1 Mutations Affecting GALT and LN Development 32

3.2 Genes Regulating the Development of Lymphoid Tissue Inducers 34

3.3 Mutations Affecting Spleen but Not LN and PP Development 35

4 Role of Receptor/Ligand Interactions

Between Fetal Hematopoietic and Mesenchymal Cells 36

4.1 TNF Family Members 36

4.2 IL-7 and IL-7R Signaling Pathway 40

4.3 Chemokines and Adhesion Molecules 42

5 Conclusions 44

References 44

Abstract During evolution, the development of secondary lymphoid organs has evolved as a strategy to promote adaptive immune responses at sites of antigen sequestration. Mesenteric lymph nodes (LNs) and Peyer's patches (PPs) are localized in proximity to mucosal surfaces, and their development is coordinated by a series of temporally and spatially regulated molecular events involving the collaboration between hematopoietic, mesenchymal, and, for PPs, epithelial cells. Transcriptional control of cellular differentiation, production of cytokines as well as adhesion molecules are mandatory for organogenesis, recruitment of mature leukocytes, and lymphoid tissue organization. Similar to fetal and neonatal organogenesis, lymphoid tissue neoformation can occur in adult individuals at sites of chronic stimulation via cytokines and TNF-family member molecules. These molecules represent new therapeutic targets to manipulate the microenvironment during autoimmune diseases.

Abbreviations

Ag

Antigen

BM

Bone marrow

CP

Cryptopatch

DC

Dendritic cell

GC

Germinal center

FDC

Follicular dendritic cell

GALT

Gut-associated lymphoid tissue

HEV

High endothelial venule

ICAM-1

Intercellular adhesion molecule 1

IEL

Intraepithelial lymphocytes

Ig

Immunoglobulin

IKK

Inhibitor of kB kinase

ILF

Isolated lymphoid follicle

IL

Interleukin

LN

Lymph node

LT

Lymphotoxin

mAb

Monoclonal antibody

MAdCAM-1

Mucosal addressin cellular adhesion molecule 1

NALT

Nasopharynx-associated lymphoid tissue

NF-kB

Nuclear factor-kB

NIK

Nuclear factor-kB-inducing kinase

NK

Natural killer cell

PNAd

Peripheral node addressin

PP

Peyer's patch

RORy

Retinoic acid-related orphan receptor y

TNF

Tumor necrosis factor

TRAF6

TNF receptor-associated factor 6

TRANCE

Tumor necrosis factor-related activation-induced cytokine

VCAM-1

Vascular cell adhesion molecule 1

VEGF

Vascular endothelial growth factor

WT

Wild type

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