Bcl10 plays a divergent role in NK cell-mediated cytotoxicity and cytokine generation.
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.
Malarkannan
Subramaniam
S
Laboratory of Molecular Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. subra.malar@bcw.edu
Regunathan
Jeyarani
J
Chu
Haiyan
H
Kutlesa
Snjezana
S
Chen
Yuhong
Y
Zeng
Hu
H
Wen
Renren
R
Wang
Demin
D
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000950:Antigens, Ly / Q000502:physiology; D000954:Antigens, Surface / Q000502:physiology; D000074018:B-Cell CLL-Lymphoma 10 Protein; D016466:CHO Cells; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007376:Interleukin-2 / Q000502:physiology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000502:physiology; D055630:Receptors, NK Cell Lectin-Like; D055607:Receptors, Natural Killer Cell; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology