Id2-, RORγt-, and LTβR-independent initiation of lymphoid organogenesis in ocular immunity

Nagatake, Takahiro; Fukuyama, Satoru; Kim, Dong Young; Goda, Kaoru; Igarashi, Osamu; Sato, Shintaro; Nochi, Tomonori; Sagara, Hiroshi; Yokota, Yoshifumi; Jetten, Anton M.; Kaisho, Tsuneyasu; Akira, Shizuo; Mimuro, Hitomi; Sasakawa, Chihiro; Fukui, Yoshihiro; Fujihashi, Kohtaro; Akiyama, Taishin; Inoue, Jun; Penninger, Josef; Kunisawa, Jun; Kiyono, Hiroshi

doi:10.1084/jem.20091436

Cited by 68 publications

(86 citation statements)

References 62 publications

(145 reference statements)

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“…M cells, a unique epithelial cell type specializing in Ag sampling, have been discovered in follicleassociated epithelium of TALT, GALT, and nasal-associated lymphoid tissue (34,38,39). The M cell-like cells found in our study after eyedrop application were depressed from adjacent epithelial cells and had irregular and longer microvilli (Figs.…”

Section: Discussionmentioning

confidence: 53%

“…Therefore, these results imply that eyedrop vaccination is unique and a safer method of mucosal vaccine delivery independent of nasal mucosa. Nagatake et al (34) showed that tear duct-associated lymphoid tissues (TALTs), which are located in the lacrimal sac, play a role in the induction of Ag-specific immune response against Ag found on the ocular surface. TALT is the site of ocular Ag uptake by M celllike cells and also the site for induction of Ag-specific IgA and CD4 + cells after ocular immunization.…”

Section: Discussionmentioning

confidence: 99%

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Eye Mucosa: An Efficient Vaccine Delivery Route for Inducing Protective Immunity

Seo

Han

Cha

et al. 2010

The Journal of Immunology

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The external part of the eye shares mucosa-associated common characteristics and is an obvious entry site for foreign Ags. We assessed the potential of eyedrop vaccination for effective delivery of vaccines against viral or bacterial infection in mice. Both OVA-specific IgG Ab in serum and IgA Ab in mucosal compartments were induced by eyedrops of OVA with cholera toxin (CT). Eyedrop vaccination of influenza A/PR/8 virus (H1N1) induced both influenza virus-specific systemic and mucosal Ab responses and protected mice completely against respiratory infection with influenza A/PR/8 virus. In addition, eyedrop vaccination of attenuated Salmonella vaccine strains induced LPS-specific Ab and complete protection against oral challenge of virulent Salmonella. Unlike with the intranasal route, eyedrop vaccinations did not redirect administered Ag into the CNS in the presence of CT. When mice were vaccinated by eyedrop, even after the occlusion of tear drainage from eye to nose, Ag-specific systemic IgG and mucosal IgA Abs could be induced effectively. Of note, eyedrops with OVA plus CT induced organogenesis of conjunctiva-associated lymphoid tissue and increased microfold cell-like cells on the conjunctiva-associated lymphoid tissue in the nictitating membrane on conjunctiva, the mucosal side of the external eye. On the basis of these findings, we propose that the eyedrop route is an alternative to mucosal routes for administering vaccines.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Eye Mucosa: An Efficient Vaccine Delivery Route for Inducing Protective Immunity

Seo

Han

Cha

et al. 2010

The Journal of Immunology

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“…In addition to the PPs, other types of mucosa-associated secondary lymphoid tissues, such as nasopharynx-associated lymphoid tissue and tear duct-associated lymphoid tissue, are identified. Interestingly, nasopharynx-associated lymphoid tissue organogenesis depends on Id2, but not Rorgt, expression (9,39), whereas tear duct-associated lymphoid tissue formation is independent of both factors (40). Because results in this study revealed that Runx1/Cbfb2 complexes act earlier than Id2 and Rorgt during differentiation of the LTi lineage cells, it is interesting to examine in the future study whether formation of another mucosaassociated secondary lymphoid tissues is impaired by loss of Runx/Cbfb complexes function.…”

Section: Discussionmentioning

confidence: 75%

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

Tachibana

Tenno

Tezuka

et al. 2011

The Journal of Immunology

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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.

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“…Tears are consistently secreted to wet the conjunctiva and cornea, and leaked to the nasal cavity via the lacrimal canaliculi, lacrimal sac, and nasolacrimal duct. The lacrimal sac in the mouse develops lymphoid follicles which are classified as part of the tear duct-associated lymphoid tissue (TALT) (27). The lymphoid follicles in mouse TALT are covered by the thinner stratified squamous epithelium which contains dispersed M cell-like cells, as detected by lectin histochemistry and a monoclonal antibody (27).…”

Section: Methodsmentioning

confidence: 99%

<b>GP2-expressing cells in the conjunctiva and tear ducts of mice: identification of a novel type of cells in the squamous stratified </b><b>epithelium </b>

et al. 2015

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GP2 is a membrane-associated secretory protein originally identified in zymogen granules of pancreatic acinar cells. Recently, this glycoprotein has attracted attention as a marker substance of M cells of Peyer's patches and for its involvement in the selective uptake of pathological bacteria via M cells. When we stained the conjunctiva and tear ducts of mice using a GP2 antibody, all goblet cells in the squamous stratified epithelium of the conjunctiva were intensely immunolabeled, while goblet cells in the intestine and airway were devoid of the immunoreactivity, indicating that the conjunctiva contains a special type of goblet cell. Further immunostaining for GP-2 labeled dispersed cells of peculiar shapes within the stratified squamous epithelium in the lacrimal canaliculi, lacrimal sac, and nasolacrimal duct. The GP2-immunoreactive cells in the tear duct projected arched or branched processes toward the basement membrane. Electron-microscopically, immunogold particles for GP2 outlined the basolateral plasma membrane of both the conjuntival goblet cells and the peculiarly shaped cells in the tear duct. Intracellularly, GP2 products of the goblet cells were localized around secretory granules in the apical cytoplasm and those of the tear duct cells inside the vesicles. The luminal contents close to apical plasma membrane were heavily labeled with immunogold particles, suggesting an exocytosis-based targeting of GP2 to the plasma membrane and its release into the lumen. The possible function of GP2 in tear ducts is discussed in relation to a defense system against invasive microoranisms and antigens.Tears contain various substances, such as lipids, mucins, ions, enzymes, and immunoglobulins. Mucins originate mostly in conjunctival goblet cells and the lacrimal glands (1, 13, 36), the latter being mucous in nature in some animals. The main and accessory lacrimal glands also secrete antimicrobial substances including lysozyme, lactoferrin, and lipocalin in both basal and reflex tear secretions (for review, 24). Secretory immunoglobulin A, the major antibody present in the tear film and tear fluid, is produced by plasma cells in cooperation with lacrimal glands and conjunctival lymphoid tissues (24). The antimicrobial enzymes, immunoglobulins, and complement factors assure immunologic functions against microorganisms and antigens. It is generally believed that conjunctival goblet cells are not directly involved in the ocular defense system. In the intestine, however, morphological studies for longer than 100 years have reported the existence of intermediate cells between goblet cells and Paneth cells, the latter a predominant cell source of antimicrobial substances in the small intestine (3). Numbers of the intermediate cells increased in the intestine of mice with abnormal Notch signaling (37) or with the infection of parasitic nematodes (15). Furthermore, goblet cells in the small intestine possess an ability to uptake luminal antigens and present them to sub-

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Id2-, RORγt-, and LTβR-independent initiation of lymphoid organogenesis in ocular immunity

Cited by 68 publications

References 62 publications

Eye Mucosa: An Efficient Vaccine Delivery Route for Inducing Protective Immunity

Eye Mucosa: An Efficient Vaccine Delivery Route for Inducing Protective Immunity

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

<b>GP2-expressing cells in the conjunctiva and tear ducts of mice: identification of a novel type of cells in the squamous stratified </b><b>epithelium </b>

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