Expression of α4β7 Integrin Defines a Distinct Pathway of Lymphoid Progenitors Committed to T Cells, Fetal Intestinal Lymphotoxin Producer, NK, and Dendritic Cells

The heteromeric lymphotoxin αβ ligand (LT) binds to the LTβ receptor (LTβR) and provides an essential trigger for lymph node (LN) development. LTβR signaling is also critical for the emergence of pathological ectopic lymph node-like structures and the maintenance of an organized splenic white pulp. To better understand the role of LT in development, the expression patterns of LTβ and LTβR mRNA were examined by in situ hybridization in the developing mouse embryo. Images of LTβ ligand expression in developing peripheral LN in the E18.5 embryo revealed a relatively early phase structure and allowed for comparative staging with LN development in rat and humans. The LTβR is expressed from E16.5 onward in respiratory, salivary, bronchial, and gastric epithelium, which may be consistent with early communication events between lymphoid elements and epithelial specialization over emerging mucosal LN. Direct comparison of mouse fetal and adult tissues by FACS analysis confirmed the elevated expression of LTBR in some embryonic epithelial layers. Therefore, surface LTBR expression may be elevated during fetal development in some epithelial layers.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Visualization of Lymphotoxin-β and Lymphotoxin-β Receptor Expression in Mouse Embryos

Browning

French

2002

“…For instance, expression of the IL-7R a-chain (IL-7Ra) enables us to identify LTi progenitors in lineage marker-negative (Lin 2 ) populations (10,11). In addition, coexpression of a4b7integrin (a4b7) with IL-7Ra in CD4 + CD3 2 cells at neonatal LN suggested that a4b7 is another marker useful for defining LTi cells (8,12,13 (14). In addition, by employing an in vitro culture system, Lin 2 a4b7 2 IL-7Ra + fetal liver population, in which B-lymphoid potential is also retained, was shown to give rise to a4b7 + IL-7Ra + cells that lacked B-lymphoid potential (13).…”

mentioning

confidence: 99%

Runx1/Cbfβ2 Complexes Are Required for Lymphoid Tissue Inducer Cell Differentiation at Two Developmental Stages

Tachibana

Tenno

Tezuka

et al. 2011

Self Cite

Hematopoietic lymphoid tissue inducer (LTi) cells are essential for the development of secondary lymphoid tissues including lymph nodes and Peyer’s patches. Two transcription factors, the helix-loop-helix inhibitor Id2 and the retinoic acid-related orphan receptor γt (Rorγt), have been shown to be crucial for LTi cell development. However, it remains unclear how the specification of multipotent hematopoietic progenitor cells toward the LTi lineage is programmed. In this study, we report impaired lymphoid tissue organogenesis in mice in which the function of Runx1/Cbfβ transcription factor complexes was attenuated by the loss of either the distal promoter-derived Runx1 or Cbfβ2 variant protein. We found that LTi progenitors in fetal liver, defined previously as a lineage marker-negative α4β7 integrin (α4β7)+ IL-7R α-chain (IL-7Rα)+ population, can be subdivided into Rorγt-expressing IL-7Rαhigh cells and nonexpressing IL-7Rαmid cells. Whereas Id2 and Rorγt are required to direct α4β7+IL-7Rαmid cells to become α4β7+IL-7Rαhigh cells, Runx1/Cbfβ2 complexes are necessary for the emergence of α4β7+IL-7Rαmid cells. In addition, the loss of Cbfβ2, but not P1-Runx1, resulted in an inefficient upregulation of Rorγt in residual α4β7+IL-7Rα+ LTi cells at anlagen. Our results thus revealed that Runx1/Cbfβ2 complexes regulate the differentiation of LTi cells at two stages: an early specification of hematopoietic progenitors toward the LTi lineage and a subsequent activation of Rorγt expression at anlagen.

“…The absence of PP and LN in these mice cannot be restored by LT/LT␤R-dependent events later in life (10,11). The cellular source of LT required for the formation of PP and LN is believed to be a bone marrow-derived, CD4 ϩ , CD3 Ϫ , non-T and non-B lymphocyte precursor, which can be a progenitor of NK cells and dendritic cells (12)(13)(14). These requirements for gestational-dependent, LT/LT␤R-dependent events appear to be universal for the formation of secondary lymphoid structures, although the formation of cervical LN and MLN in the absence of these signals has been reported (15).…”

mentioning

confidence: 99%

Isolated Lymphoid Follicle Formation Is Inducible and Dependent Upon Lymphotoxin-Sufficient B Lymphocytes, Lymphotoxin β Receptor, and TNF Receptor I Function

Lorenz

Chaplin

McDonald

et al. 2003

256

362

The gastrointestinal mucosa contains a complex network of lymphoid compartments that have evolved to efficiently protect the host from invading pathogens. Recently, an additional lymphoid structure resembling Peyer’s patches (PP) in composition and architecture has been identified in the murine small intestine, the isolated lymphoid follicle (ILF). In this study we examine the nature and factors required for ILF formation. We observed a spectrum of structures fitting the previous descriptions of ILFs, ranging from clusters of B220+ cells (which we have termed immature ILFs) to well-organized lymphoid nodules (which we have termed mature ILFs). Here we demonstrate that that similar to PP formation, ILF formation requires lymphotoxin (LT)- and LTβ receptor-dependent events. However unlike PP formation, the LT- and LTβ receptor-dependent events required for ILF formation can occur in adulthood and require LT-sufficient B lymphocytes. We demonstrate that mature ILF formation occurs in response to lumenal stimuli, including normal bacterial flora, and requires TNF receptor I function. These findings suggest that ILFs are organized intestinal lymphoid structures whose formation can be induced and whose mass can be expanded in response to mucosal challenges.