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J Clin Immunol. 2010 Jul;30(4):531-8. doi: 10.1007/s10875-010-9382-9. Epub 2010 Mar 27.

TL1A selectively enhances IL-12/IL-18-induced NK cell cytotoxicity against NK-resistant tumor targets.

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  • 1Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., D4063, Los Angeles, CA, 90048, USA.

Abstract

INTRODUCTION:

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.

DISCUSSION:

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.

CONCLUSION:

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.

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