Distinct roles in NKT cell maturation and function for the different transcription factors in the classical NF-κB pathway.
The nuclear factor (NF)-κB signalling pathway is known to be critical for natural killer T (NKT) cell differentiation; however, the role of individual NF-κB transcription factors and the precise developmental stages that they control remain unclear. We have investigated the influence of the classical NF-κB transcription factors NF-κB1, c-Rel and RelA on NKT cell development and function, using gene-deleted mice. Individually, none of these factors were essential for the requirement of NF-κB signalling in early NKT cell development before NK1.1 expression, in contrast to earlier reports in which the classical NF-κB pathway was globally disrupted. Instead, we found that each factor played a non-redundant role in later stages of NKT cell maturation and function. Although NF-κB1 deficiency resulted in a moderate reduction in mature NK1.1+ NKT cells, this was found to be more subtle than previously reported. RelA deficiency had a more profound effect on the NK1.1+ stage of NKT cell development, whereas c-Rel-deficient mice had normal NKT cell numbers. All three factors (NF-κB1, RelA and c-Rel) were necessary for normal NKT cell cytokine production. Notably, IL-17, which is produced by a specific subset of NKT cells (NKT-17 cells), defined as NK1.1(-)CD4(-), was not impaired by a lack of these individual NF-κB transcription factors, nor was this subset depleted, suggesting that NKT-17 cells are regulated independently of the NF-κB pathway. Thus, individual NF-κB family members have a largely redundant role in early NKT cell development, but each of them has an important and distinct role in NKT cell maturation and/or function.
Stankovic
Sanda
S
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
Gugasyan
Raffi
R
Kyparissoudis
Konstantinos
K
Grumont
Raelene
R
Banerjee
Ashish
A
Tsichlis
Philip
P
Gerondakis
Steve
S
Godfrey
Dale I
DI
D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000172:deficiency / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D051996:Transcription Factor RelA / Q000378:metabolism*
D016207:Cytokines; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA