Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin

Adriana Flores-Langarica*, Charlotte Cook, Katarzyna Müller Luda, Emma K. Persson, Jennifer L. Marshall, Nonantzin Beristain-Covarrubias, Juan Carlos Yam-Puc, Madelene Dahlgren, Jenny J. Persson, Satoshi Uematsu, Shizuo Akira, Ian R. Henderson, Bengt Johansson Lindbom, William Agace, Adam F. Cunningham

*Corresponding author for this work

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    Abstract

    Systemic immunization with soluble flagellin (sFliC) from Salmonella Typhimurium induces mucosal responses, offering potential as an adjuvant platform for vaccines. Moreover, this engagement of mucosal immunity is necessary for optimal systemic immunity, demonstrating an interaction between these two semi-autonomous immune systems. Although TLR5 and CD103+CD11b+ cDC2 contribute to this process, the relationship between these is unclear in the early activation of CD4+ T cells and the development of antigen-specific B cell responses. In this work, we use TLR5-deficient mice and CD11c-cre.Irf4fl/fl mice (which have reduced numbers of cDC2, particularly intestinal CD103+CD11b+ cDCs), to address these points by studying the responses concurrently in the spleen and the mesenteric lymph nodes (MLN). We show that CD103+CD11b+ cDC2 respond rapidly and accumulate in the MLN after immunization with sFliC in a TLR5-dependent manner. Furthermore, we identify that whilst CD103+CD11b+ cDC2 are essential for the induction of primary T and B cell responses in the mucosa, they do not play such a central role for the induction of these responses in the spleen. Additionally, we show the involvement of CD103+CD11b+ cDC2 in the induction of Th2-associated responses. CD11c-cre.Irf4fl/fl mice showed a reduced primary FliC-specific Th2-associated IgG1 responses, but enhanced Th1-associated IgG2c responses. These data expand our current understanding of the mucosal immune responses promoted by sFliC and highlights the potential of this adjuvant for vaccine usage by taking advantage of the functionality of mucosal CD103+CD11b+ cDC2.

    Original languageEnglish
    Article number2409
    JournalFrontiers in Immunology
    Volume9
    Number of pages9
    ISSN1664-3224
    DOIs
    Publication statusPublished - 2018

    Keywords

    • CDC2
    • Dendritic cells
    • Flagellin
    • Immune response
    • Mucosa

    Cite this

    Flores-Langarica, A., Cook, C., Luda, K. M., Persson, E. K., Marshall, J. L., Beristain-Covarrubias, N., ... Cunningham, A. F. (2018). Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin. Frontiers in Immunology, 9, [2409]. https://doi.org/10.3389/fimmu.2018.02409
    Flores-Langarica, Adriana ; Cook, Charlotte ; Luda, Katarzyna Müller ; Persson, Emma K. ; Marshall, Jennifer L. ; Beristain-Covarrubias, Nonantzin ; Yam-Puc, Juan Carlos ; Dahlgren, Madelene ; Persson, Jenny J. ; Uematsu, Satoshi ; Akira, Shizuo ; Henderson, Ian R. ; Lindbom, Bengt Johansson ; Agace, William ; Cunningham, Adam F. / Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin. In: Frontiers in Immunology. 2018 ; Vol. 9.
    @article{00f13ffbb0aa49e992c8e8a54f766891,
    title = "Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin",
    abstract = "Systemic immunization with soluble flagellin (sFliC) from Salmonella Typhimurium induces mucosal responses, offering potential as an adjuvant platform for vaccines. Moreover, this engagement of mucosal immunity is necessary for optimal systemic immunity, demonstrating an interaction between these two semi-autonomous immune systems. Although TLR5 and CD103+CD11b+ cDC2 contribute to this process, the relationship between these is unclear in the early activation of CD4+ T cells and the development of antigen-specific B cell responses. In this work, we use TLR5-deficient mice and CD11c-cre.Irf4fl/fl mice (which have reduced numbers of cDC2, particularly intestinal CD103+CD11b+ cDCs), to address these points by studying the responses concurrently in the spleen and the mesenteric lymph nodes (MLN). We show that CD103+CD11b+ cDC2 respond rapidly and accumulate in the MLN after immunization with sFliC in a TLR5-dependent manner. Furthermore, we identify that whilst CD103+CD11b+ cDC2 are essential for the induction of primary T and B cell responses in the mucosa, they do not play such a central role for the induction of these responses in the spleen. Additionally, we show the involvement of CD103+CD11b+ cDC2 in the induction of Th2-associated responses. CD11c-cre.Irf4fl/fl mice showed a reduced primary FliC-specific Th2-associated IgG1 responses, but enhanced Th1-associated IgG2c responses. These data expand our current understanding of the mucosal immune responses promoted by sFliC and highlights the potential of this adjuvant for vaccine usage by taking advantage of the functionality of mucosal CD103+CD11b+ cDC2.",
    keywords = "CDC2, Dendritic cells, Flagellin, Immune response, Mucosa",
    author = "Adriana Flores-Langarica and Charlotte Cook and Luda, {Katarzyna M{\"u}ller} and Persson, {Emma K.} and Marshall, {Jennifer L.} and Nonantzin Beristain-Covarrubias and Yam-Puc, {Juan Carlos} and Madelene Dahlgren and Persson, {Jenny J.} and Satoshi Uematsu and Shizuo Akira and Henderson, {Ian R.} and Lindbom, {Bengt Johansson} and William Agace and Cunningham, {Adam F.}",
    year = "2018",
    doi = "10.3389/fimmu.2018.02409",
    language = "English",
    volume = "9",
    journal = "Frontiers in Immunology",
    issn = "1664-3224",
    publisher = "Frontiers Research Foundation",

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    Flores-Langarica, A, Cook, C, Luda, KM, Persson, EK, Marshall, JL, Beristain-Covarrubias, N, Yam-Puc, JC, Dahlgren, M, Persson, JJ, Uematsu, S, Akira, S, Henderson, IR, Lindbom, BJ, Agace, W & Cunningham, AF 2018, 'Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin', Frontiers in Immunology, vol. 9, 2409. https://doi.org/10.3389/fimmu.2018.02409

    Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin. / Flores-Langarica, Adriana; Cook, Charlotte; Luda, Katarzyna Müller; Persson, Emma K.; Marshall, Jennifer L.; Beristain-Covarrubias, Nonantzin; Yam-Puc, Juan Carlos; Dahlgren, Madelene; Persson, Jenny J.; Uematsu, Satoshi; Akira, Shizuo; Henderson, Ian R.; Lindbom, Bengt Johansson; Agace, William; Cunningham, Adam F.

    In: Frontiers in Immunology, Vol. 9, 2409, 2018.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin

    AU - Flores-Langarica, Adriana

    AU - Cook, Charlotte

    AU - Luda, Katarzyna Müller

    AU - Persson, Emma K.

    AU - Marshall, Jennifer L.

    AU - Beristain-Covarrubias, Nonantzin

    AU - Yam-Puc, Juan Carlos

    AU - Dahlgren, Madelene

    AU - Persson, Jenny J.

    AU - Uematsu, Satoshi

    AU - Akira, Shizuo

    AU - Henderson, Ian R.

    AU - Lindbom, Bengt Johansson

    AU - Agace, William

    AU - Cunningham, Adam F.

    PY - 2018

    Y1 - 2018

    N2 - Systemic immunization with soluble flagellin (sFliC) from Salmonella Typhimurium induces mucosal responses, offering potential as an adjuvant platform for vaccines. Moreover, this engagement of mucosal immunity is necessary for optimal systemic immunity, demonstrating an interaction between these two semi-autonomous immune systems. Although TLR5 and CD103+CD11b+ cDC2 contribute to this process, the relationship between these is unclear in the early activation of CD4+ T cells and the development of antigen-specific B cell responses. In this work, we use TLR5-deficient mice and CD11c-cre.Irf4fl/fl mice (which have reduced numbers of cDC2, particularly intestinal CD103+CD11b+ cDCs), to address these points by studying the responses concurrently in the spleen and the mesenteric lymph nodes (MLN). We show that CD103+CD11b+ cDC2 respond rapidly and accumulate in the MLN after immunization with sFliC in a TLR5-dependent manner. Furthermore, we identify that whilst CD103+CD11b+ cDC2 are essential for the induction of primary T and B cell responses in the mucosa, they do not play such a central role for the induction of these responses in the spleen. Additionally, we show the involvement of CD103+CD11b+ cDC2 in the induction of Th2-associated responses. CD11c-cre.Irf4fl/fl mice showed a reduced primary FliC-specific Th2-associated IgG1 responses, but enhanced Th1-associated IgG2c responses. These data expand our current understanding of the mucosal immune responses promoted by sFliC and highlights the potential of this adjuvant for vaccine usage by taking advantage of the functionality of mucosal CD103+CD11b+ cDC2.

    AB - Systemic immunization with soluble flagellin (sFliC) from Salmonella Typhimurium induces mucosal responses, offering potential as an adjuvant platform for vaccines. Moreover, this engagement of mucosal immunity is necessary for optimal systemic immunity, demonstrating an interaction between these two semi-autonomous immune systems. Although TLR5 and CD103+CD11b+ cDC2 contribute to this process, the relationship between these is unclear in the early activation of CD4+ T cells and the development of antigen-specific B cell responses. In this work, we use TLR5-deficient mice and CD11c-cre.Irf4fl/fl mice (which have reduced numbers of cDC2, particularly intestinal CD103+CD11b+ cDCs), to address these points by studying the responses concurrently in the spleen and the mesenteric lymph nodes (MLN). We show that CD103+CD11b+ cDC2 respond rapidly and accumulate in the MLN after immunization with sFliC in a TLR5-dependent manner. Furthermore, we identify that whilst CD103+CD11b+ cDC2 are essential for the induction of primary T and B cell responses in the mucosa, they do not play such a central role for the induction of these responses in the spleen. Additionally, we show the involvement of CD103+CD11b+ cDC2 in the induction of Th2-associated responses. CD11c-cre.Irf4fl/fl mice showed a reduced primary FliC-specific Th2-associated IgG1 responses, but enhanced Th1-associated IgG2c responses. These data expand our current understanding of the mucosal immune responses promoted by sFliC and highlights the potential of this adjuvant for vaccine usage by taking advantage of the functionality of mucosal CD103+CD11b+ cDC2.

    KW - CDC2

    KW - Dendritic cells

    KW - Flagellin

    KW - Immune response

    KW - Mucosa

    U2 - 10.3389/fimmu.2018.02409

    DO - 10.3389/fimmu.2018.02409

    M3 - Journal article

    VL - 9

    JO - Frontiers in Immunology

    JF - Frontiers in Immunology

    SN - 1664-3224

    M1 - 2409

    ER -