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Keywords: lymphocyte, cytotoxicity, Rab, exocytosis, myosin V. To assess the possibility that T cell hyperproliferation in Griscelli's patients bearing Rab27a mutations is due to a decrease in surface expression of CTLA4 secondary to defective granule exocytosis, we examined TcR-induced CTLA-4 surface expression in activated T cells from ashen and C3H mice. Because this polarization is difficult to quantify, we cannot exclude the possibility that Rab27a contributes to the efficiency of this process, but we can conclude that it is not absolutely required for granule polarization to occur. These results show that the FasL—Fas cytotoxicity pathway is normal in ashen cells, whereas the granule exocytosis pathway is defective. CTLs from ashen mice were compared with C3H controls for their ability to lyse Fas-negative L target cells using redirected cytotoxicity. Figure 4. In vitro cytotoxicity of cytotoxic T and NK lymphocytes from ashen and dilute mice. Ashen mice contain a single point mutation that prevents the proper splicing of Rab27a transcripts Wilson et al. Henkart, National Institutes of Health, Bldg. Cytotoxic T lymphocytes CTLs and natural killer NK cells lyse target cells by exocytosing specialized secretory granules containing perforin and granzymes into a synapse-like junction that forms between the lymphocyte and the bound target cell Henkart et al. Thus, although Rab27a is required for the TcR-triggered exocytosis of granules containing preformed secretory products, it is not required for TcR-induced gene expression and exocytosis of the vesicles associated with the constitutive secretory pathway. Acknowledgments We thank Drs. Figure 1. Granzyme B and perforin levels as determined by Western blot analysis Fig. After TcR ligation, T cells express CTLA-4 on their surface, which engages B7 family ligands and generates negative signals ending the interaction with antigen presenting cells. Solid circles are hidden by solid squares symbols in this graph. NK activity was measured on splenocytes harvested 24 h after i. Together with defective NK cytotoxicity Fig. Gillian Griffiths for communication of unpublished results. Together, these experiments show that ashen CTLs have an intact FasL—Fas cytotoxicity pathway even though their granule exocytosis cytotoxicity pathway is abolished, and argue against a general defect in TcR signaling in the ashen CTL. Figure 3. Importantly, although both types of Griscelli's patients exhibit partial albinism, only those with mutations in Rab27a exhibit T cell hyperproliferation and defects in lymphocyte cytotoxicity Menasche et al. Hammer, III. The defect in the granule exocytosis cytotoxicity exhibited by ashen CTLs could also be due to the inability of granules to polarize to the site of target cell contact Kupfer and Singer We found that ashen CTLs can polarize their secretory granules upon contact with anti-CD3—coated beads data not shown. The defect in the granule exocytosis cytotoxicity pathway in ashen cytotoxic lymphocytes could be due to a failure in the delivery of the critical effector proteins perforin and granzymes to the granules, or in the formation of the granules themselves, especially since platelets from ashen mice exhibit a dramatic reduction in the number of dense granules Wilson et al. These results also suggest that the FasL detectable in perforin-containing CTL granules Bossi and Griffiths did not contribute significantly to the functional ligand on the effector cell surface in these experiments. After antibody staining, samples were washed and mounted using antifade mounting medium SlowFade; Molecular Probes. A similar deficiency was observed using allospecific EL-4 target cells to measure direct TcR—mediated cytotoxicity data not shown. Death of the target cell requires perforin-dependent membrane permeabilization, followed by granzyme-dependent proteolysis of critical cytoplasmic substrates Henkart et al. National Center for Biotechnology Information , U. Numbers of both thymocytes and splenocytes were identical in C3H and ashen mice data not shown. Bar, 2. Unless otherwise specified, anti—mouse lymphocyte surface antibodies were purchased from BD PharMingen, as was recombinant IL The sources of other reagents were as follows: recombinant IL-2 Boehringer ; polystyrene beads 6. Figure 2. John A. B6 mice heterozygous for the dilute allele d l20J , a functional null allele for the myosin Va heavy chain, were a gift of Neal Copeland and Nancy Jenkins National Cancer Institute. J Cell Biol. Bar, 4. A Granzyme B, red. Recently, the mouse coat color mutant ashen was shown to be caused by a mutation in Rab27a Wilson et al. We thank Drs. In an effort to define in a more precise way the role of Rab27a in lymphocyte-mediated cytoxicity, we have characterized CTLs from ashen mice with regard to granule biogenesis, distribution, and release, and with regard to cytotoxic function in vitro via the granule-mediated and Fas pathways. These results also strengthen the case that TcR signaling is normal in ashen T cells. Our results also shed light on the molecular etiology of the fatal human hyperproliferative syndrome resulting from mutations in Rab27a. Cells were incubated sequentially for 1 h each in primary and secondary antibodies in blocking buffer containing 0.

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. However, hourly today luton weather shown in Fig.

Dilute and ashen mice exhibit identical degrees of coat color dilution and identical defects in the distribution of melanosomes within melanocytes Wilson et al. Open in a separate window.

Viable cells were isolated by lympholyte separation medium Cedarlane Laboratoriesand either used at this stage, or cultured for another 48 h in the presence of 0. However, comparable cells from ashen mice showed no secretion of this granule marker by either subpopulation.

Introduction Cytotoxic T lymphocytes CTLs and natural killer NK cells lyse target cells by exocytosing specialized secretory granules containing perforin and granzymes into a synapse-like junction that forms between the lymphocyte and the bound target cell Henkart et al. Thus, exocytosis of cytotoxic lymphocyte granules does read more appear to require myosin Va, in contrast to the generation of a proper igg ashen accumulation of melanosomes within melanocytes, which requires both myosin Va and Rab27a.

Pierre A. Henkart: vog. Secretion was determined from enzyme activity in supernatants, expressed as a percentage of levels in Triton X cell lysates.

These results imply that Igg ashen is expressed in both T cell and NK lymphocyte lineages and is required for cytotoxicity via the granule exocytosis cytotoxicity pathway. Ashen mice exhibit a reduction in coat color intensity, an abnormal perinuclear distribution of melanosomes, the pigment-producing organelle of melanocytes, and a profound deficit in dense granules and their components within platelets.

Identical results to those shown in Fig. One such disease is Griscelli's syndrome, a rare autosomal recessive disease characterized by partial albinism in conjunction with other symptoms Klein et al.

Elias K. The Western blot in Fig. Together, these data indicate that the defective killing by ashen CTLs is not due to obvious defects in T cell maturation or to a general defect in the expansion of precursors during effector cell differentiation.

To determine whether the defective killing by ashen CTLs was due to a defect in T cell maturation, we compared T cell phenotypes of ashen and C3H spleens and thymus.

Haddada Xufeng Wub John A. This article has been cited by other articles igg ashen PMC.

Although a small fraction of patients have mutations in myosin Va, the majority have mutations in Rab27a, a relatively uncharacterized Rab family member previously identified in melanocytes and cells igg ashen hematopoetic origin Nagata et al.

Anti-CD3—coated beads were prepared by washing 6. B Rab 27a, green. Our results argue that the principal site of action of Rab27a in the immune system is in cytotoxic lymphocytes and that it functions at a late step in the fusion of granules with the plasma membrane.

Although their granule-mediated cytotoxicity pathway is profoundly defective, ashen CTLs displayed a normal FasL—Fas cytotoxicity pathway. These data further extend the findings of defective granule exocytosis in activated T cells from Rab27a-deficient humans Menasche et al.

References Bossi G. Igg ashen concanamycin A was used to abolish the granule exocytosis cytotoxicity igg ashen Kataoka et al. This makes it unlikely that a defect in FasL surface expression due to compromised degranulation contributes to the T cell hyperproliferation in Griselli's patients with mutations in Rab27a, as might have been predicted from defects in FasL itself Wu et al.

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.

Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells.

Although the cause of this disease was originally identified as a mutation in the unconventional myosin, myosin Va Pastural et al. CTL granule exocytosis induced by TcR cross-linking can be measured by release of granule enzymes into the supernatant after incubation on anti-CD3—coated surfaces. Therefore, we conclude that Rab27a is not required for the biogenesis of effector granules in CTLs. C Colocalization of granzyme B and Rab 27a yellow. Unlike the case with platelet dense granule biogenesis, granules form normally in ashen CTLs and contain a normal complement of mediators. Figure 5. Thus, a defect in CTLA-4 surface expression due to defective granule exoctyosis is unlikely to explain the hyperproliferation of T cells seen in Griscelli's syndrome patients with Rab27a mutations. Journal List J Cell Biol v. Several human diseases have been identified that involve defects in lymphocyte-mediated cytotoxicity via the granule exocytosis pathway. In addition to this granule-mediated pathway, CTLs also possess a second cytotoxic pathway in which T cell receptor TcR engagement induces expression of Fas ligand, which crosslinks Fas on the target cell surface, triggering apoptosis. As shown in Fig. In conclusion, our results show that Rab27a functions at a late stage in the regulated secretion of granule mediators, but not in the constitutive secretory pathway. Abstract 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. This lack of detectable Rab27a protein is compatible with the severe defect in processing of Rab27a transcripts seen by reverse transcriptase—PCR in tissues from ashen mice Wilson et al. Author information Article notes Copyright and License information Disclaimer. Henkart a. Activity levels were determined from the linear portion of plots of activity versus cell number. CTLA-4 knockout mice have a lethal lymphoproliferative disease Waterhouse et al. Projected images are shown. These data confirm in mice the results obtained in humans with mutations in either myosin Va or Rab27a, where only the latter exhibit defects in lymphocyte-mediated cytotoxicity Menasche et al.