Journal
CELLULAR IMMUNOLOGY
Volume 255, Issue 1-2, Pages 82-92Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.cellimm.2008.12.001
Keywords
T cells; Cytotoxic; Cytotoxicity; Perforin; Cathepsin B; Inhibitor; Protein disulfide isomerase
Categories
Funding
- NIH [RO1CA38942, T32CA09563, P20RR016463]
- Eagles Research Award
- University of Nevada
- Reno Graduate Student Association
- NATIONAL CANCER INSTITUTE [R01CA038942, T32CA009563] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR016463] Funding Source: NIH RePORTER
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Perforin, a membrane-permeabilizing protein, is important to T cell cytotoxic action. Perforin has potential to damage the T cell in the endoplasmic reticulum (ER), is sequestered in granules, and later is exocytosed to kill cells. In the ER and after exocytosis, calcium and pH favor perforin activity. We found a novel perforin inhibitor associated with cytotoxic T cell granules and termed it Cytotoxic Regulatory Protein 2 (CxRP2). CxRP2 blocked lysis by granule extracts, recombinant perforin and T cells. Its effects lasted for hours. CxRP2 was calcium stable and refractory to inhibitors of granzyme and cathepsin proteases. Through mass spectrometric analysis of active 50-100 kDa proteins, we identified CxRP2 candidates. Protein disulfide isomerase A3 was the strongest candidate but was unavailable for testing; however, protein disulfide isomerase A1 had CxRP2 activity. Our results indicate that protein disulfide isomerases, in the ER or elsewhere, may protect T cells from their own perforin. (C) 2008 Elsevier Inc. All rights reserved.
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