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Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells.

Halle S, Dujardin HC, Bakocevic N, Fleige H, Danzer H, Willenzon S, Suezer Y, Hämmerling G, Garbi N, Sutter G, Worbs T, Förster R - J. Exp. Med. (2009)

Bottom Line: After intratracheal application, in vitro-differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently activate antigen-specific T cells, as revealed by two-photon microscopy.Furthermore, the lung-specific depletion of DCs in mice that express the diphtheria toxin receptor under the control of the CD11c promoter interferes with BALT maintenance.Collectively, these data identify BALT as tertiary lymphoid structures supporting the efficient priming of T cell responses directed against unrelated airborne antigens while crucially requiring DCs for its sustained presence.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany.

ABSTRACT
Mucosal vaccination via the respiratory tract can elicit protective immunity in animal infection models, but the underlying mechanisms are still poorly understood. We show that a single intranasal application of the replication-deficient modified vaccinia virus Ankara, which is widely used as a recombinant vaccination vector, results in prominent induction of bronchus-associated lymphoid tissue (BALT). Although initial peribronchiolar infiltrations, characterized by the presence of dendritic cells (DCs) and few lymphocytes, can be found 4 d after virus application, organized lymphoid structures with segregated B and T cell zones are first observed at day 8. After intratracheal application, in vitro-differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently activate antigen-specific T cells, as revealed by two-photon microscopy. Furthermore, the lung-specific depletion of DCs in mice that express the diphtheria toxin receptor under the control of the CD11c promoter interferes with BALT maintenance. Collectively, these data identify BALT as tertiary lymphoid structures supporting the efficient priming of T cell responses directed against unrelated airborne antigens while crucially requiring DCs for its sustained presence.

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Induction of BALT after mucosal infection with MVA. (A–H) C57/BL6 mice were infected i.n. with 107 IU MVA, and at the time points indicated (days after infection), lung sections were analyzed by fluorescence microscopy applying mAb and DAPI as indicated. Representative sections from three to six mice analyzed for each time point derived from two to three different experiments are shown. Bars, 100 µm. (I) The number of BALT structures per entire central lung section was determined by microscopy (means + SD; n = 3–5 animals per time point; pooled data are derived from six independent experiments). b, bronchioles; v, vessels.
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fig1: Induction of BALT after mucosal infection with MVA. (A–H) C57/BL6 mice were infected i.n. with 107 IU MVA, and at the time points indicated (days after infection), lung sections were analyzed by fluorescence microscopy applying mAb and DAPI as indicated. Representative sections from three to six mice analyzed for each time point derived from two to three different experiments are shown. Bars, 100 µm. (I) The number of BALT structures per entire central lung section was determined by microscopy (means + SD; n = 3–5 animals per time point; pooled data are derived from six independent experiments). b, bronchioles; v, vessels.

Mentions: We have recently shown that i.n. infection with the mouse γ-herpesvirus MHV-68 induces BALT in mice and that BALT actually serves as a reservoir of latent MHV-68 (Kocks et al., 2009). To address the question of whether latent or continuous reinfection of host cells with virus is required for the induction and/or maintenance of BALT, we tested the replication-deficient poxvirus MVA for its ability to induce BALT. Although the peribronchiolar space in lungs of untreated mice contained only few CD11c+ cells and hardly any lymphocytes (Fig. 1 A and not depicted), a massive perivascular and peribronchiolar infiltration of CD11c+ cells could be observed 4 d after i.n. application of 107 infectious units (IU) MVA (Fig. 1 B). At day 8 after infection, B and T cells had been recruited to CD11c+ cell–rich areas (Fig. 1, C and D). Although in some areas B and T cells were still scattered diffusely around vessels and bronchioles (Fig. 1 C) at this time point, we also frequently observed areas in which B cells started to segregate toward the center of BALT structures (Fig. 1 D). By day 12, large areas of BALT had been formed. Frequently, CD11c+ cells were found surrounding the structures (Fig. 1 E), whereas B and T cells exhibited various degrees of clustering (Fig. 1 F). At day 28 after infection, the MVA-induced BALT displayed a pronounced segregation into T and B cell–rich areas (Fig. 1 G). In this differentiated BALT, DCs were found to reside primarily in the T cell areas (Fig. 1 H). Quantitative analysis revealed that BALT structures were most abundantly present between days 8 and 12 after infection but could still be detected at relatively high frequencies even 28 d after virus application (Fig. 1 I). Collectively, these data demonstrate that a single i.n. application of the replication-deficient MVA is sufficient to induce the long-lasting presence of highly organized BALT, and that the accumulation of CD11c+ cells around vessels and bronchioles represents an early event in its formation.


Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells.

Halle S, Dujardin HC, Bakocevic N, Fleige H, Danzer H, Willenzon S, Suezer Y, Hämmerling G, Garbi N, Sutter G, Worbs T, Förster R - J. Exp. Med. (2009)

Induction of BALT after mucosal infection with MVA. (A–H) C57/BL6 mice were infected i.n. with 107 IU MVA, and at the time points indicated (days after infection), lung sections were analyzed by fluorescence microscopy applying mAb and DAPI as indicated. Representative sections from three to six mice analyzed for each time point derived from two to three different experiments are shown. Bars, 100 µm. (I) The number of BALT structures per entire central lung section was determined by microscopy (means + SD; n = 3–5 animals per time point; pooled data are derived from six independent experiments). b, bronchioles; v, vessels.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2806625&req=5

fig1: Induction of BALT after mucosal infection with MVA. (A–H) C57/BL6 mice were infected i.n. with 107 IU MVA, and at the time points indicated (days after infection), lung sections were analyzed by fluorescence microscopy applying mAb and DAPI as indicated. Representative sections from three to six mice analyzed for each time point derived from two to three different experiments are shown. Bars, 100 µm. (I) The number of BALT structures per entire central lung section was determined by microscopy (means + SD; n = 3–5 animals per time point; pooled data are derived from six independent experiments). b, bronchioles; v, vessels.
Mentions: We have recently shown that i.n. infection with the mouse γ-herpesvirus MHV-68 induces BALT in mice and that BALT actually serves as a reservoir of latent MHV-68 (Kocks et al., 2009). To address the question of whether latent or continuous reinfection of host cells with virus is required for the induction and/or maintenance of BALT, we tested the replication-deficient poxvirus MVA for its ability to induce BALT. Although the peribronchiolar space in lungs of untreated mice contained only few CD11c+ cells and hardly any lymphocytes (Fig. 1 A and not depicted), a massive perivascular and peribronchiolar infiltration of CD11c+ cells could be observed 4 d after i.n. application of 107 infectious units (IU) MVA (Fig. 1 B). At day 8 after infection, B and T cells had been recruited to CD11c+ cell–rich areas (Fig. 1, C and D). Although in some areas B and T cells were still scattered diffusely around vessels and bronchioles (Fig. 1 C) at this time point, we also frequently observed areas in which B cells started to segregate toward the center of BALT structures (Fig. 1 D). By day 12, large areas of BALT had been formed. Frequently, CD11c+ cells were found surrounding the structures (Fig. 1 E), whereas B and T cells exhibited various degrees of clustering (Fig. 1 F). At day 28 after infection, the MVA-induced BALT displayed a pronounced segregation into T and B cell–rich areas (Fig. 1 G). In this differentiated BALT, DCs were found to reside primarily in the T cell areas (Fig. 1 H). Quantitative analysis revealed that BALT structures were most abundantly present between days 8 and 12 after infection but could still be detected at relatively high frequencies even 28 d after virus application (Fig. 1 I). Collectively, these data demonstrate that a single i.n. application of the replication-deficient MVA is sufficient to induce the long-lasting presence of highly organized BALT, and that the accumulation of CD11c+ cells around vessels and bronchioles represents an early event in its formation.

Bottom Line: After intratracheal application, in vitro-differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently activate antigen-specific T cells, as revealed by two-photon microscopy.Furthermore, the lung-specific depletion of DCs in mice that express the diphtheria toxin receptor under the control of the CD11c promoter interferes with BALT maintenance.Collectively, these data identify BALT as tertiary lymphoid structures supporting the efficient priming of T cell responses directed against unrelated airborne antigens while crucially requiring DCs for its sustained presence.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany.

ABSTRACT
Mucosal vaccination via the respiratory tract can elicit protective immunity in animal infection models, but the underlying mechanisms are still poorly understood. We show that a single intranasal application of the replication-deficient modified vaccinia virus Ankara, which is widely used as a recombinant vaccination vector, results in prominent induction of bronchus-associated lymphoid tissue (BALT). Although initial peribronchiolar infiltrations, characterized by the presence of dendritic cells (DCs) and few lymphocytes, can be found 4 d after virus application, organized lymphoid structures with segregated B and T cell zones are first observed at day 8. After intratracheal application, in vitro-differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently activate antigen-specific T cells, as revealed by two-photon microscopy. Furthermore, the lung-specific depletion of DCs in mice that express the diphtheria toxin receptor under the control of the CD11c promoter interferes with BALT maintenance. Collectively, these data identify BALT as tertiary lymphoid structures supporting the efficient priming of T cell responses directed against unrelated airborne antigens while crucially requiring DCs for its sustained presence.

Show MeSH
Related in: MedlinePlus