Journal
JOURNAL OF IMMUNOLOGY
Volume 179, Issue 6, Pages 3752-3762Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.179.6.3752
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Funding
- NHLBI NIH HHS [R01 HL073284] Funding Source: Medline
- NIAID NIH HHS [U19 AI062627-01, R01 AI52327] Funding Source: Medline
- PHS HHS [N01-HHSN26600500032C, R01 A1064826-01] Funding Source: Medline
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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 Bc110. 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 Carmal-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 Bc110 represents an exclusive molecular switch that links the upstream receptor-mediated signaling to cytokine and chemokine generations.
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