IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors.
The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3(-)NKp46(+) cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1(+), Ly49(+)) but also a large CD127(+)NK1.1(-) subset of lymphoid tissue inducer (LTi)-like Rorc(+) cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3(-)NKp46(+) subsets. Gut CD3(-)NKp46(+) cells were related to LTi and NK cells in requiring the transcriptional inhibitor Id2 for normal development. Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1(+) cells within the gut but had no effect on absolute numbers of the CD127(+)NK1.1(-)Rorc(+) subset of CD3(-)NKp46(+) cells. In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3(-)NKp46(+)NK1.1(-) cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1(+) cells. Finally, in vivo fate-mapping experiments demonstrated that intestinal NK1.1(+)CD127(-) cells are not the progeny of Rorc-expressing progenitors, indicating that CD127(+)NK1.1(-)Rorc(+) cells are not canonical NK cell precursors. These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46(+) cell subsets.
Cytokines and Lymphoid Development Unit, Institut Pasteur, 75724 Paris, France.
Naoko
N
Satoh-Takayama
Sarah
S
Lesjean-Pottier
Paulo
P
Vieira
Shinichiro
S
Sawa
Gerard
G
Eberl
Christian A J
CA
Vosshenrich
James P
JP
Di Santo
D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D006801:Humans; D007113:Immunity, Innate; D051797:Inhibitor of Differentiation Protein 2 / Q000276:immunology / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000276:immunology; D051379:Mice; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology; D000097043:Interleukin-22
D000950:Antigens, Ly; D017252:CD3 Complex; D051797:Inhibitor of Differentiation Protein 2; D019409:Interleukin-15; D015851:Interleukin-7; D007378:Interleukins; D055627:Natural Cytotoxicity Triggering Receptor 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000097043:Interleukin-22; C497452:Idb2 protein, mouse; C118384:Ncr1 protein, mouse; C539901:Rorc protein, mouse