A role for Blimp1 in the transcriptional network controlling natural killer cell maturation.
Natural killer (NK) cells are innate lymphocytes capable of immediate effector functions including cytokine production and cytotoxicity. Compared with B and T cells, the factors that control the peripheral maturation of NK cells are poorly understood. We show that Blimp1, a transcriptional repressor required for the differentiation of plasma cells and short-lived effector T cells, is expressed by NK cells throughout their development. Interleukin 15 (IL-15) is required for the early induction of Blimp1 in NK cells, with expression increasing in the most mature subsets of mouse and human NK cells. We show that Blimp1 is required for NK-cell maturation and homeostasis and for regulating their proliferative potential. It is also essential for high granzyme B expression, but not for most cytokine production and cytotoxicity. Surprisingly, interferon regulatory factor 4 (IRF4) and B-cell lymphoma 6 (Bcl6), 2 transcription factors crucial for the regulation of Blimp1 in B and T cells, are largely dispensable for Blimp1 expression in NK cells. T-bet deficiency, however, leads to attenuated Blimp1 expression. We have identified NK cells as the first hematopoietic cell type in which the IRF4-Blimp1-Bcl6 regulatory axis is not in operation, highlighting the distinct nature of the NK-cell gene-regulatory network.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. kallies@wehi.edu.au
Axel
A
Kallies
Sebastian
S
Carotta
Nicholas D
ND
Huntington
Nicholas J
NJ
Bernard
David M
DM
Tarlinton
Mark J
MJ
Smyth
Stephen L
SL
Nutt
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation; D000098815:T-bet Transcription Factor
D016207:Cytokines; D017931:DNA Primers; D019409:Interleukin-15; C513258:Prdm1 protein, mouse; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1