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The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection

Nature Immunology volume 15, pages 546–553 (2014)Cite this article

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Abstract

Natural killer (NK) cells are innate lymphocytes that exhibit many features of adaptive immunity, including clonal proliferation and long-lived memory. Here we demonstrate that the BTB-ZF transcription factor Zbtb32 (also known as ROG, FAZF, TZFP and PLZP) was essential for the proliferative burst and protective capacity of virus-specific NK cells. Signals from proinflammatory cytokines were both necessary and sufficient to induce high expression of Zbtb32 in NK cells. Zbtb32 facilitated NK cell proliferation during infection by antagonizing the anti-proliferative factor Blimp-1 (Prdm1). Our data support a model in which Zbtb32 acts as a cellular 'hub' through which proinflammatory signals instruct a 'proliferation-permissive' state in NK cells, thereby allowing their prolific expansion in response to viral infection.

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Figure 1: Zbtb32 is highly upregulated in NK cells during viral infection.
Figure 2: Zbtb32 is required for protective antiviral NK cell responses.
Figure 3: Zbtb32 is dispensable for NK cell activation, maturation and expression of effector molecules.
Figure 4: Zbtb32 is essential for NK cell expansion during viral infection.
Figure 5: Zbtb32 regulates NK cell proliferation after MCMV infection.
Figure 6: Inflammatory cytokines are necessary and sufficient for maximal Zbtb32 expression in NK cells.
Figure 7: Zbtb32 promotes NK cell proliferation by antagonizing Blimp-1.

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Acknowledgements

We thank members of the Sun lab for technical support and experimental assistance, members of the Memorial Sloan-Kettering NK club for insightful comments and helpful discussions, A. Rudensky, M. van den Brink, M. Li, L. Lanier (University of California San Francisco), D. Sant'Angelo (Rutgers University) and L. Denzin (Rutgers University) for sharing antibodies and flow cytometry resources and for providing expertise critical to this study and manuscript, G. Gasteiger, K. Schluns (M.D. Anderson) and U. Koszinowski (Max von Pettenkofer-Institute) for providing many of the parent and recombinant viruses used in our study, S. Way (University of Minnesota) for providing femurs from Il12rb2−/− × Ifnar1−/− mice for use in making bone marrow chimeras, the Immunological Genome Consortium for providing the microarray data used in this study26, and J.P. Houchins and his team at R&D Systems for providing the experimental anti-Zbtb32 flow cytometry antibody used in this study. A.M.B. was supported by US National Institutes of Health T32 award (CA009149). J.C.S. was supported by the Searle Scholars Program, the Cancer Research Institute, and grants from the National Institutes of Health (AI085034 and AI100874).

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Authors and Affiliations

  1. Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Aimee M Beaulieu, Carolyn L Zawislak & Joseph C Sun

  2. Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Toshinori Nakayama

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  1. Aimee M Beaulieu
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  2. Carolyn L Zawislak
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  3. Toshinori Nakayama
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Contributions

A.M.B. and C.L.Z. performed the experiments; T.N. provided the Zbtb32−/− mice and feedback on the manuscript; A.M.B. and J.C.S. designed the study and wrote the manuscript.

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Correspondence to Joseph C Sun.

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Integrated supplementary information

Supplementary Figure 1 Zbtb32 protein is upregulated in NK cells during MCMV infection.

Intranuclear Zbtb32 expression in splenic Ly49H+ NK cells from WT or Zbtb32–/– animals following MCMV infection (n = 3 animals per time point). Representative of 2 independent experiments.

Supplementary Figure 2 Zbtb32 is dispensable for IFN-γ production in vitro and cytotoxicity in vivo.

(a) WT or Zbtb32–/– splenocytes were stimulated for 18 h, then IFN-γ+ NK cells were identified by flow cytometry (n = 3 biological replicates per group). Data are representative of 2 – 3 experiments. (b) Equal numbers of CFSE-labeled splenocytes from WT (CFSElo), m157-transgenic (CFSEmid), or B2m–/– (CFSEhi) animals were co-transferred into WT (left) or Zbtb32–/– (right) recipients. After 24 h, the percentage of remaining cells from each population was determined in the spleen. Data are representative of 4 – 6 animals per genotype from 2 independent experiments.

Supplementary Figure 3 Zbtb32-deficiency impairs viral antigen-independent NK cell proliferation during infection.

(a) Schematic of adoptive transfer experiments. Equal numbers of WT (CD45.1+) and Zbtb32–/–(CD45.2+) Ly49H+ NK cells were co-transferred into Ly49H-deficient hosts one day prior to infection with MCMV. (b) Expression of Zbtb32 mRNA in Ly49H+ and Ly49H– NK cells sorted from the spleens of WT animals on day 0 or 2 p.i. with MCMV (n = 7 animals per time point from 2 pooled experiments). Data are shown as fold expression relative to Ly49H+ NK cells at day 0 p.i. (c) Equal numbers of CFSE-labeled WT and Zbtb32–/– NK cells were transferred into congenic Ly49H-deficient hosts. CFSE dilution (left panel: WT, black; Zbtb32–/–, gray) and percentage of cells that divided > 5 rounds (right panel; n = 3 mice) in the Ly49H+ and Ly49H- transferred NK cells from the spleens of MCMV-infected animals on day 5 p.i. Representative of 2 independent experiments. (d) As in (c), except animals were infected with MCMVΔm157 and data are shown for Ly49H+ NK cells only (n = 3 mice). Representative of 2 independent experiments.

Supplementary Figure 4 NK cells develop normally in Zbtb32–/– animals.

(a) Percentage of NK cells in various organs in naïve WT or Zbtb32–/– mice (n = 3 mice per genotype). (b) Percentage (left panel) and absolute number (right panel) of CD122+Lin– cells that are pre-NK cells (pNK; DX5–NK1.1- ) or mature NK cells (mNK; DX5+NK1.1+) in the bone marrow of naïve WT or Zbtb32–/– mice (n = 3 mice per genotype). (c) Percentage of NK cells expressing indicated Ly49 NK receptors in naïve WT or Zbtb32–/– mice (n = 3 mice per genotype). (d) Expression of various activating receptors on NK cells from naïve WT or Zbtb32–/– mice (n = 3 mice per genotype). All panels are representative of 2 independent experiments.

Supplementary Figure 5 Zbtb32 is required in a cell-intrinsic manner for NK cell proliferation during viral infection.

Equal numbers of WT and Zbtb32–/– Ly49H+ NK cells from WT:Zbtb32–/– mixed bone marrow chimeras were co-transferred into Ly49H-deficient hosts. The percentage of transferred WT (CD45.1+) and Zbtb32–/– (CD45.2+) Ly49H+ NK cells in the spleen on days 8 and 24 p.i. with MCMV. Day 0 panel shows the percentage of each population in the spleens of the chimeric donors prior to transfer. Representative data from n = 3 mice per time point.

Supplementary Figure 6 Zbtb32–/–NK cells upregulate pSTATs, T-bet and GATA-3 but down-regulate Bcl-6, after MCMV infection.

(a) Splenic WT and Zbtb32–/– NK cells were co-transferred into Ly49H-deficient mice. Expression of intracellular phosphorylated STAT1, STAT3, STAT4, T-bet, and GATA-3 on transferred Ly49H+ NK cells in the spleen on day 3 p.i. with MCMV (n = 3 animals). Shaded histograms show expression in uninfected controls (n = 1 animal). Representative of 2 – 3 independent experiments. (b) Bcl6 mRNA abundance in splenic WT Ly49H+ NK cells sorted on indicated days p.i. with MCMV (n = 3 per time point), shown as fold expression relative to day 0.

Supplementary Figure 7 Zbtb32 regulates the proliferative burst of Ly49H-activated NK cells during MCMV infection.

Zbtb32 acts downstream of the IL-12 receptor and STAT4 (in addition to other proinflammatory cytokine signals) to antagonize Blimp-1 and instruct a “proliferation permissive” state in NK cells.

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Beaulieu, A., Zawislak, C., Nakayama, T. et al. The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection. Nat Immunol 15, 546–553 (2014). https://doi.org/10.1038/ni.2876

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