Central Role of Core Binding Factor β2 in Mucosa-Associated Lymphoid Tissue Organogenesis in Mouse

Takahiro Nagatake,Shintaro Sato,Michiko Shimojou,Hideaki Okura,Naomi Matsumoto,Masashi Tachibana,Hiroshi Kiyono,Jun Kunisawa,Satoshi Fukuyama,Hidehiko Suzuki,Ichiro Taniuchi,Kosei Ito

doi:10.1371/journal.pone.0127460

Abstract

Mucosa-associated lymphoid tissue (MALT) is a group of secondary and organized lymphoid tissue that develops at different mucosal surfaces. Peyer’s patches (PPs), nasopharynx-associated lymphoid tissue (NALT), and tear duct-associated lymphoid tissue (TALT) are representative MALT in the small intestine, nasal cavity, and lacrimal sac, respectively. A recent study has shown that transcriptional regulators of core binding factor (Cbf) β2 and promotor-1-transcribed Runt-related transcription factor 1 (P1-Runx1) are required for the differentiation of CD3−CD4+CD45+ lymphoid tissue inducer (LTi) cells, which initiate and trigger the developmental program of PPs, but the involvement of this pathway in NALT and TALT development remains to be elucidated. Here we report that Cbfβ2 plays an essential role in NALT and TALT development by regulating LTi cell trafficking to the NALT and TALT anlagens. Cbfβ2 was expressed in LTi cells in all three types of MALT examined. Indeed, similar to the previous finding for PPs, we found that Cbfβ2−/− mice lacked NALT and TALT lymphoid structures. However, in contrast to PPs, NALT and TALT developed normally in the absence of P1-Runx1 or other Runx family members such as Runx2 and Runx3. LTi cells for NALT and TALT differentiated normally but did not accumulate in the respective lymphoid tissue anlagens in Cbfβ2−/− mice. These findings demonstrate that Cbfβ2 is a central regulator of the MALT developmental program, but the dependency of Runx proteins on the lymphoid tissue development would differ among PPs, NALT, and TALT.

Highlights

The developmental program of secondary lymphoid tissues is initiated by interaction between hematopoietic lymphoid tissue inducer (LTi) cells and stromal lymphoid tissue organizer (LTo) cells [1]
Consistent with our previous reports [16,17,18], we detected an accumulation of CD3−CD4+ LTi cells in anlagen of Mucosa-associated lymphoid tissue (MALT) at the period of MALT organogenesis in each case, Peyer’s patches (PPs) anlagen of the small intestine on E17 and nasopharynx-associated lymphoid tissue (NALT) and tear duct-associated lymphoid tissue (TALT) anlagens on neonatal day 10 (D10) (Fig 1)
The results revealed that CD3−CD4+CD45+ NALTi and TALTi cells were present in the nasal tissues and tear duct compartment of Cbfβ2−/− mice (S2 Fig), indicating that Cbfβ2 might play critical roles in NALT and TALT development independently from the known LTi cell differentiation (e.g., PPi cells)

Summary

Introduction

The developmental program of secondary lymphoid tissues is initiated by interaction between hematopoietic lymphoid tissue inducer (LTi) cells and stromal lymphoid tissue organizer (LTo) cells [1]. Neuron-derived retinoic acid induces the initial expression of C-X-C motif chemokine ligand (CXCL) 13 in LTo cells [9], which express vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 [10], thereby inducing migration of LTi cells into the lymphoid tissue anlagen. LTi cell–derived LTα1β2 stimulates LTβR-expressing LTo cells through alternative NF-κB pathways, which induces production of large amounts of lymphoid chemokines (e.g., CXCL13, CCL19, and CCL21) and adhesion molecules (e.g., VCAM-1 and ICAM-1)[13]. This process induces migration of large numbers of LTi cells as well as conventional leukocytes into lymphoid tissue anlagen. The cytokine and chemokine signals, triggered by LTi cells and LTo cells, form a positive feedback loop that promotes the generation of the organizing center of lymphoid tissues [1]

Methods

Results

Conclusion