The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo

Vicky Louise Morrison, Matthew MacPherson, Terhi Savinko, Hwee San Lek, Alan Prescott, Susanna Carola Fagerholm (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    27 Citations (Scopus)

    Abstract

    Kindlin-3 is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, which is characterized by deficient integrin-mediated adhesion of leukocytes and platelets. However, the specific roles of kindlin-3–?2-integrin interactions in T-cell adhesion and homing and immune responses in vivo remain unclear. Here, we show that the TTT motif in ?2 integrins controls kindlin-3 binding. Mutation of the kindlin-3 binding site in ?2 integrins caused a loss of firm adhesion of T cells under both static and shear flow conditions and a reduction of T-cell homing to lymph nodes in vivo. However, atomic force microscopy studies of integrin-ligand bonds revealed that initial ligand binding could still occur, and 2-dimensional T-cell migration was reduced but not abolished by the TTT/AAA mutation in the ?2 integrin. Importantly, dendritic cell–mediated T-cell activation in vivo was normal in TTT/AAA ?2 integrin knock-in mice. Our results reveal a selective role of the kindlin-3–integrin association for lymphocyte functions in vivo; the integrin–kindlin-3 interaction is particularly important in adhesion strengthening under shear flow, and for T-cell homing to lymph nodes, but dispensable for T cell activation which occurs in a shear-free environment.
    Original languageEnglish
    Pages (from-to)1428-1436
    Number of pages9
    JournalBlood
    Volume122
    Issue number8
    DOIs
    Publication statusPublished - 22 Aug 2013

    Fingerprint

    T-cells
    Integrins
    Chemical activation
    T-Lymphocytes
    Adhesion
    Shear flow
    Lymph Nodes
    Ligands
    Mutation
    Inborn Genetic Diseases
    Lymphocytes
    Atomic Force Microscopy
    Cell adhesion
    Platelets
    Cell Adhesion
    Cell Movement
    Atomic force microscopy
    Leukocytes
    Blood Platelets
    Binding Sites

    Keywords

    • Animals
    • Antigens, CD18
    • CD4-Positive T-Lymphocytes
    • Cell Adhesion
    • Cell Movement
    • Cytoskeletal Proteins
    • Glutathione Transferase
    • HEK293 Cells
    • Humans
    • Lymphocyte Activation
    • Membrane Proteins
    • Mice
    • Mice, Inbred C57BL
    • Mice, Transgenic
    • Neoplasm Proteins
    • T-Lymphocytes

    Cite this

    Morrison, Vicky Louise ; MacPherson, Matthew ; Savinko, Terhi ; San Lek, Hwee ; Prescott, Alan ; Fagerholm, Susanna Carola. / The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo. In: Blood. 2013 ; Vol. 122, No. 8. pp. 1428-1436.
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    abstract = "Kindlin-3 is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, which is characterized by deficient integrin-mediated adhesion of leukocytes and platelets. However, the specific roles of kindlin-3–?2-integrin interactions in T-cell adhesion and homing and immune responses in vivo remain unclear. Here, we show that the TTT motif in ?2 integrins controls kindlin-3 binding. Mutation of the kindlin-3 binding site in ?2 integrins caused a loss of firm adhesion of T cells under both static and shear flow conditions and a reduction of T-cell homing to lymph nodes in vivo. However, atomic force microscopy studies of integrin-ligand bonds revealed that initial ligand binding could still occur, and 2-dimensional T-cell migration was reduced but not abolished by the TTT/AAA mutation in the ?2 integrin. Importantly, dendritic cell–mediated T-cell activation in vivo was normal in TTT/AAA ?2 integrin knock-in mice. Our results reveal a selective role of the kindlin-3–integrin association for lymphocyte functions in vivo; the integrin–kindlin-3 interaction is particularly important in adhesion strengthening under shear flow, and for T-cell homing to lymph nodes, but dispensable for T cell activation which occurs in a shear-free environment.",
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    year = "2013",
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    The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo. / Morrison, Vicky Louise; MacPherson, Matthew; Savinko, Terhi; San Lek, Hwee; Prescott, Alan; Fagerholm, Susanna Carola (Lead / Corresponding author).

    In: Blood, Vol. 122, No. 8, 22.08.2013, p. 1428-1436.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo

    AU - Morrison, Vicky Louise

    AU - MacPherson, Matthew

    AU - Savinko, Terhi

    AU - San Lek, Hwee

    AU - Prescott, Alan

    AU - Fagerholm, Susanna Carola

    PY - 2013/8/22

    Y1 - 2013/8/22

    N2 - Kindlin-3 is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, which is characterized by deficient integrin-mediated adhesion of leukocytes and platelets. However, the specific roles of kindlin-3–?2-integrin interactions in T-cell adhesion and homing and immune responses in vivo remain unclear. Here, we show that the TTT motif in ?2 integrins controls kindlin-3 binding. Mutation of the kindlin-3 binding site in ?2 integrins caused a loss of firm adhesion of T cells under both static and shear flow conditions and a reduction of T-cell homing to lymph nodes in vivo. However, atomic force microscopy studies of integrin-ligand bonds revealed that initial ligand binding could still occur, and 2-dimensional T-cell migration was reduced but not abolished by the TTT/AAA mutation in the ?2 integrin. Importantly, dendritic cell–mediated T-cell activation in vivo was normal in TTT/AAA ?2 integrin knock-in mice. Our results reveal a selective role of the kindlin-3–integrin association for lymphocyte functions in vivo; the integrin–kindlin-3 interaction is particularly important in adhesion strengthening under shear flow, and for T-cell homing to lymph nodes, but dispensable for T cell activation which occurs in a shear-free environment.

    AB - Kindlin-3 is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, which is characterized by deficient integrin-mediated adhesion of leukocytes and platelets. However, the specific roles of kindlin-3–?2-integrin interactions in T-cell adhesion and homing and immune responses in vivo remain unclear. Here, we show that the TTT motif in ?2 integrins controls kindlin-3 binding. Mutation of the kindlin-3 binding site in ?2 integrins caused a loss of firm adhesion of T cells under both static and shear flow conditions and a reduction of T-cell homing to lymph nodes in vivo. However, atomic force microscopy studies of integrin-ligand bonds revealed that initial ligand binding could still occur, and 2-dimensional T-cell migration was reduced but not abolished by the TTT/AAA mutation in the ?2 integrin. Importantly, dendritic cell–mediated T-cell activation in vivo was normal in TTT/AAA ?2 integrin knock-in mice. Our results reveal a selective role of the kindlin-3–integrin association for lymphocyte functions in vivo; the integrin–kindlin-3 interaction is particularly important in adhesion strengthening under shear flow, and for T-cell homing to lymph nodes, but dispensable for T cell activation which occurs in a shear-free environment.

    KW - Animals

    KW - Antigens, CD18

    KW - CD4-Positive T-Lymphocytes

    KW - Cell Adhesion

    KW - Cell Movement

    KW - Cytoskeletal Proteins

    KW - Glutathione Transferase

    KW - HEK293 Cells

    KW - Humans

    KW - Lymphocyte Activation

    KW - Membrane Proteins

    KW - Mice

    KW - Mice, Inbred C57BL

    KW - Mice, Transgenic

    KW - Neoplasm Proteins

    KW - T-Lymphocytes

    U2 - 10.1182/blood-2013-02-484998

    DO - 10.1182/blood-2013-02-484998

    M3 - Article

    VL - 122

    SP - 1428

    EP - 1436

    JO - Blood

    JF - Blood

    SN - 0006-4971

    IS - 8

    ER -