Granulysin activates antigen-presenting cells through TLR4 and acts as an immune alarmin

Blood. 2010 Nov 4;116(18):3465-74. doi: 10.1182/blood-2010-03-273953. Epub 2010 Jul 21.


Granulysin (GNLY), an antimicrobial protein present in the granules of human cytotoxic T lymphocytes and natural killer (NK) cells, is produced as an intact 15-kDa form that is cleaved to yield a 9-kDa form. Alarmins are endogenous mediators that can induce recruitment and activation of antigen-presenting cells (APCs) and consequently promote the generation of immune response. We hypothesized that GNLY might function as an alarmin. Here, we report that both 9- and 15-kDa forms of recombinant GNLY-induced in vitro chemotaxis and activation of both human and mouse dendritic cells (DCs), recruited inflammatory leucocytes, including APCs in mice, and promoted antigen-specific immune responses upon coadministration with an antigen. GNLY-induced APC recruitment and activation required the presence of Toll-like receptor 4. The observed activity of recombinant GNLY was not due to endotoxin contamination. The capability of the supernatant of GNLY-expressing HuT78 cells to activate DC was blocked by anti-GNLY antibodies. Finally we present evidence that supernatants of degranulated human NK92 or primary NK cells also activated DCs in a GNLY- and Toll-like receptor 4-dependent manner, indicating the physiologic relevance of our findings. Thus, GNLY is the first identified lymphocyte-derived alarmin capable of promoting APC recruitment, activation, and antigen-specific immune response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / administration & dosage
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Cells, Cultured
  • Chemotaxis*
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Female
  • Humans
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology
  • Leukocytes / cytology
  • Leukocytes / immunology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / immunology
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / immunology
  • Toll-Like Receptor 4 / immunology*


  • Antigens, Differentiation, T-Lymphocyte
  • GNLY protein, human
  • Myeloid Differentiation Factor 88
  • Recombinant Proteins
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4