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Defective Granule Exocytosis in Rab27a-Deficient Lymphocytes from Ashen Mice
Journal article   Open access   Peer reviewed

Defective Granule Exocytosis in Rab27a-Deficient Lymphocytes from Ashen Mice

Elias K. Haddad, Xufeng Wu, John A. Hammer and Pierre A. Henkart
The Journal of cell biology, v 152(4), pp 835-842
19 Feb 2001
DOI: https://doi.org/10.1083/jcb.152.4.835
PMID: 11266473
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://rupress.org/jcb/article-pdf/152/4/835/1296948/0011045.pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1083/jcb.152.4.835View
Published, Version of Record (VoR) Open

Abstract

cytotoxicity exocytosis lymphocyte myosin V Original Rab
Because mutations in Rab27a have been linked to immune defects in humans, we have examined cytotoxic lymphocyte function in ashen mice, which contain a splicing mutation in Rab27a. Ashen cytotoxic T lymphocytes (CTLs) showed a >90% reduction in lytic activity on Fas-negative target cells compared with control C3H CTLs, and ashen natural killer cell activity was likewise diminished. Although their granule-mediated cytotoxicity pathway is profoundly defective, ashen CTLs displayed a normal FasL–Fas cytotoxicity pathway. The CD4/8 phenotype of ashen T cells and their proliferative responses were similar to controls. Ashen CTLs had normal levels of perforin and granzymes A and B and normal-appearing perforin-positive granules, which polarized upon interaction of the CTLs with anti–CD3-coated beads. However, rapid anti–CD3-induced granule secretion was drastically defective in both CD8 + and CD4 + T cells from ashen mice. This defect in exocytosis was not observed in the constitutive pathway, as T cell receptor–stimulated interferon-γ secretion was normal. Based on these results and our demonstration that Rab27a colocalizes with granzyme B-positive granules and is undetectable in ashen CTLs, we conclude that Rab27a is required for a late step in granule exocytosis, compatible with current models of Rab protein function in vesicle docking and fusion.

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Cell Biology
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