Faculty Collaboration Database

Bcl10 plays a divergent role in NK cell-mediated cytotoxicity and cytokine generation. J Immunol 2007 Sep 15;179(6):3752-62

Date

09/06/2007

Pubmed ID

17785812

DOI

10.4049/jimmunol.179.6.3752

Scopus ID

2-s2.0-35748981185 (requires institutional sign-in at Scopus site)   37 Citations

Abstract

Activating receptors such as NKG2D and Ly49D mediate a multitude of effector functions including cytotoxicity and cytokine generation in NK cells. However, specific signaling events that are responsible for the divergence of distinct effector functions have yet to be determined. In this study, we show that lack of caspase recruitment domain-containing protein Bcl10 significantly affected receptor-mediated cytokine and chemokine generation, but not cytotoxicity against tumor cells representing "missing-self" or "induced-self." Lack of Bcl10 completely abrogated the generation of GM-CSF and chemokines and it significantly reduced the generation of IFN-gamma (>75%) in NK cells. Commitment, development, and terminal maturation of NK cells were largely unaffected in the absence of Bcl10. Although IL-2-activated NK cells could mediate cytotoxicity to the full extent, the ability of the freshly isolated NK cells to mediate cytotoxicity was somewhat reduced. Therefore, we conclude that the Carma1-Bcl10-Malt1 signaling axis is critical for cytokine and chemokine generation, although it is dispensable for cytotoxic granule release depending on the activation state of NK cells. These results indicate that Bcl10 represents an exclusive "molecular switch" that links the upstream receptor-mediated signaling to cytokine and chemokine generations.

Author List

Malarkannan S, Regunathan J, Chu H, Kutlesa S, Chen Y, Zeng H, Wen R, Wang D

Authors

Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Animals
Antigens, Ly
Antigens, Surface
B-Cell CLL-Lymphoma 10 Protein
CHO Cells
Cell Differentiation
Cell Line, Tumor
Chemokines
Cricetinae
Cricetulus
Cytokines
Cytotoxicity, Immunologic
Immunity, Innate
Interleukin-2
Killer Cells, Natural
Lectins, C-Type
Mice
Mice, Inbred C57BL
Mice, Knockout
NK Cell Lectin-Like Receptor Subfamily A
NK Cell Lectin-Like Receptor Subfamily B
NK Cell Lectin-Like Receptor Subfamily K
Receptors, Immunologic
Receptors, NK Cell Lectin-Like
Receptors, Natural Killer Cell
Self Tolerance