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)

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    29 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

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    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

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