Basic StudiesThe Human Cathelicidin, LL-37, Induces Granzyme-mediated Apoptosis in Regulatory T CellsMader, Jamie S.*; Ewen, Catherine*; Hancock, Robert E.W.†; Bleackley, Robert C.*Author Information *Department of Biochemistry, School of Molecular and Systems Medicine, Faculty of Medicine, University of Alberta, Edmonton, Alberta †Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada Supported by Genome Canada, Genome BC and Genome Prairie for the “Pathogenomics of Innate Immunity” research program, the Canadian Institute of Health Research, the Canadian Cancer Society, and the Foundation for National Institutes of Health through the Grand Challenges in Global Health initiative. R. Chris Bleackley is a Medical Scientist of the AHFMR, and a Canada Research Chair. Jamie S. Mader was supported by a postdoctoral award from AHFMR. The authors have no conflicting financial interests. All authors have declared that there are no financial conflicts of interest with regard to this work. Reprints: Jamie S. Mader, Department of Biochemistry, School of Molecular and Systems Medicine, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada (e-mail: email@example.com). Received July 19, 2010 Accepted November 14, 2010 Journal of Immunotherapy: April 2011 - Volume 34 - Issue 3 - p 229–235 doi: 10.1097/CJI.0b013e318207ecdf Buy Metrics Abstract LL-37 is a human cationic host defense peptide (antimicrobial peptide) belonging to the cathelicidin family of peptides. In this study, LL-37 was shown to kill stimulated and nonstimulated CD4+CD25+FoxP3+ T cells (regulatory T cells; Tregs) through apoptosis, while having no cytotoxic effect on CD4+CD25− T cells at the same LL-37 concentrations. Of interest, Tregs were much more sensitive to LL-37 than many other cells, dying at 10-fold lower concentrations than other cell types tested. LL-37 exposure resulted in DNA fragmentation, chromatin condensation, and apoptotic body formation, all indicative of an apoptotic form of cell death. The importance of granzyme family members in the apoptosis of Tregs after LL-37 treatment was analyzed by using C57Bl/6 lymphocytes obtained from mice that were homozygous for null mutations in the granzyme B gene, and both the granzyme A and B genes. Granzyme A and granzyme B were both shown to play a role in LL-37-induced apoptosis of Tregs. Further analysis showed that apoptosis occurred primarily through caspase-dependent apoptosis at high LL-37 concentrations. However, grA-dependent/caspase-independent cell death was also observed. This suggests that LL-37 induces apoptosis in Tregs through multiple different mechanisms, initiated by the LL-37-induced leakage of granzymes from cytolytic granules. Our results imply that LL-37 administered at the site of a tumor could influence the adaptive antitumor immune response by killing Tregs and thus inhibiting their suppressor activity. © 2011 Lippincott Williams & Wilkins, Inc.