TL1A selectively enhances IL-12/IL-18-induced NK cell cytotoxicity against NK-resistant tumor targets.
BACKGROUND
TL1A (TNFSF15) augments IFN-gamma production by IL-12/IL-18 responsive human T cells. Its ligand, death domain receptor 3 (DR3), is induced by activation on T and NK cells. Although IL-12/IL-18 induces DR3 expression on most NK cells, addition of TL1A minimally increases IFN-gamma production.


METHODS
(51)Chromium release and flow cytometric analysis were used to determine whether the TL1A-DR3 pathway is implicated in tumor cell lysis. Our aim was to determine whether the TL1A-DR3 pathway is implicated in tumor cell lysis.


RESULTS
TL1A had no additional effect on IL-12/IL-18-induced cytotoxicity against an NK-susceptible tumor (K562); however, it promoted cytotoxicity against NK-resistant targets susceptible to lysis only by activated NK cells.


CONCLUSIONS
With IL-12/IL-18 activation, TL1A increased CD107a expression on NK cells which led to enhanced lysis of Daudi by PBMC and purified NK cells. To a lesser degree, TL1A increased lysis of colorectal adenocarcinoma epithelial derived lines (WiDr and SW837) by IL-12/IL-18-activated cells.


CONCLUSIONS
TL1A increased cytotoxicity of IL-12/IL-18-activated NK cells against target cells dependent on NK activation for lysis and could function in vivo as a key co-activator of NK cytotoxicity.
Heidemann
Stephanie C
SC
Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., D4063, Los Angeles, CA, 90048, USA.
Chavez
Valerie
V
Landers
Carol J
CJ
Kucharzik
Torsten
T
Prehn
John L
JL
Targan
Stephan R
SR
D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1; D009369:Neoplasms / Q000276:immunology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000276:immunology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000276:immunology*
D020382:Interleukin-18; D052118:Lysosomal-Associated Membrane Protein 1; D053219:Receptors, Tumor Necrosis Factor, Member 25; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D018664:Interleukin-12