Perforin is essential for CTL expansion by tumor secreted gp96-Ig (CROSBI ID 485464)
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Podaci o odgovornosti
Štrbo, Nataša ; Yamazaki, Koichi ; Ohata, June ; Zimmerman, Zachary ; Rukavina, Daniel ; Podack, Eckhard
engleski
Perforin is essential for CTL expansion by tumor secreted gp96-Ig
It is widely accepted that cellular immunotherapy of solid tumors relies heavily on the capacity of class I MHC-restricted cytotoxic T lymphocytes (CTL) to eliminate tumor cells. Target cell killing by CTLs involves the induction of cell death by two major mechanisms: through death receptors and through the perforin/granzyme pathway. Perforin-dependent cytotoxicity is a major effector activity of CD8+ MHC classI-restricted T cells and NK cells. Activated CD8 CTL and NK cells are important barriers to the development of tumors. In order to determine cellular and molecular mechanisms of NK and CTL expansion to secreted gp96-Ig in vivo we utilized the TCR transgenic adoptive transfer system: TCR transgenic CD8 (OT1) specific for the ovalbumin derived peptide SIINFEKL presented by Kb were transferred into syngeneic (C57Bl/6) mice and, after two days, stimulated by immunization of mice with 1 million gp96-Ig secreting EG7 cells. The expansion of OT1 and NK was determined at different time points with the Kb-SIINFEKL tetramer and by surface staining of NK markers by flow cytometry. To determine whether two major cytotoxicity mediators: perforin and IFN-gamma are required for CTL expansion by tumor secreted gp96-Ig, perforin knock out (PKO) and IFN-gamma knock out (GKO) mice were analyzed for their ability to support NK as well as OT1 expansion in response to EG7-gp96-Ig. Our results show that absence of either perforin or IFN-gamma completely abolished both OT1 and NK expansion, less than 3% of OT1 in the CD8 gate. In control wild type C57Bl/6 mice OT1 expanded to 25% and NK cells to 30% in response to EG7gp96-Ig. In contrast to perforin Fas-Ligand is not required for OT1 expansion, since OT1 and NK cells expand in gld mice while cdd (perforin/fas-L double deficient) mice did not support expansion. Reconstitution of PKO mice with perforin containing NK cells allowed OT1 expansion to a level comparable to OT1 expansion in wild type mice. We can conclude that NK activation and production of perforin is a prerequisite for CTL expansion by secreted heat shock protein gp96-Ig.
Heat shock; Proteins; gp96; CD8; NK; NKT; Perforin
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Podaci o prilogu
225-x.
2002.
objavljeno
Podaci o matičnoj publikaciji
Abstract book
San Francisco (CA):
Podaci o skupu
93rd AACR Annual Meetings 2002
poster
06.04.2002-10.04.2002
San Francisco (CA), Sjedinjene Američke Države