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© The Rockefeller University Press, 0021-9525/2001//835 $5.00
The Journal of Cell Biology, Volume 152, Number 4, , 2001 835-842

Defective Granule Exocytosis in Rab27a-Deficient Lymphocytes from Ashen Mice

^a Experimental Immunology Branch, National Cancer Institute; , and
^b Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892
National Institutes of Health, Bldg. 10, Rm. 4B36, Bethesda, MD 20892-1360.(301) 496-0887(301) 435-6404

ph8j{at}nih.gov

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- 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.

Key Words: lymphocyte • cytotoxicity • Rab • exocytosis • myosin V

© 2001 The Rockefeller University Press

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