TY - JOUR
T1 - Differential regulation of transcription factor T-bet induction during NK cell development and T helper-1 cell differentiation
AU - Fang, Difeng
AU - Cui, Kairong
AU - Cao, Yaqiang
AU - Zheng, Mingzhu
AU - Kawabe, Takeshi
AU - Hu, Gangqing
AU - Khillan, Jaspal S.
AU - Li, Dan
AU - Zhong, Chao
AU - Jankovic, Dragana
AU - Sher, Alan
AU - Zhao, Keji
AU - Zhu, Jinfang
N1 - Funding Information:
We thank Drs. John J. O’Shea and Ronald N. Germain for their critical reading of the manuscript. We thank Steven L. Reiner for providing the Tbx21 fl/fl mice, Takeshi Egawa and Dan R. Littman for providing the RUNX3-YFP mice, Juan Carlos Zúñiga-Pflücker for providing OP9 and OP9-DL1 cell lines, Ke Weng and the NIAID Flow Cytometry Section for cell sorting, the NIH Tetramer Core Facility for the tetramer reagents, and the NHLBI DNA Sequencing Core facility for sequencing the ChIP-seq and DNase-seq libraries. This work is supported by the Division of Intramural Research of the NIAID (grant 1ZIA-AI-001169 ) and the NHLBI (grant 1ZIA-HL-006030 ).
Funding Information:
We thank Drs. John J. O'Shea and Ronald N. Germain for their critical reading of the manuscript. We thank Steven L. Reiner for providing the Tbx21fl/fl mice, Takeshi Egawa and Dan R. Littman for providing the RUNX3-YFP mice, Juan Carlos Z??iga-Pfl?cker for providing OP9 and OP9-DL1 cell lines, Ke Weng and the NIAID Flow Cytometry Section for cell sorting, the NIH Tetramer Core Facility for the tetramer reagents, and the NHLBI DNA Sequencing Core facility for sequencing the ChIP-seq and DNase-seq libraries. This work is supported by the Division of Intramural Research of the NIAID (grant 1ZIA-AI-001169) and the NHLBI (grant 1ZIA-HL-006030). D.F. and J.Z. conceived the project. D.F. performed the majority of the experiments. K.C. contributed to ChIP-seq and DNase-seq experiments. Y.C. and G.H. performed bioinformatic analysis. M.Z. and C.Z. performed some animal experiments. T.K. and D.J. helped on some T.gondii-infection-related experiments. D.L. performed some retroviral-infection-related experiments. J.S.K. helped generate mutant mouse strains through CRISPR-Cas9. C.Z. D.J. A.S. and K.Z. provided critical advices to the project and edited the manuscript. D.F. and J.Z. wrote the manuscript. J.Z. supervised the project. The authors declare no competing interests.
Publisher Copyright:
© 2022
PY - 2022/4/12
Y1 - 2022/4/12
N2 - Adaptive CD4+ T helper cells and their innate counterparts, innate lymphoid cells, utilize an identical set of transcription factors (TFs) for their differentiation and functions. However, similarities and differences in the induction of these TFs in related lymphocytes are still elusive. Here, we show that T helper-1 (Th1) cells and natural killer (NK) cells displayed distinct epigenomes at the Tbx21 locus, which encodes T-bet, a critical TF for regulating type 1 immune responses. The initial induction of T-bet in NK precursors was dependent on the NK-specific DNase I hypersensitive site Tbx21-CNS-3, and the expression of the interleukin-18 (IL-18) receptor; IL-18 induced T-bet expression through the transcription factor RUNX3, which bound to Tbx21-CNS-3. By contrast, signal transducer and activator of transcription (STAT)-binding motifs within Tbx21-CNS-12 were critical for IL-12-induced T-bet expression during Th1 cell differentiation both in vitro and in vivo. Thus, type 1 innate and adaptive lymphocytes utilize distinct enhancer elements for their development and differentiation.
AB - Adaptive CD4+ T helper cells and their innate counterparts, innate lymphoid cells, utilize an identical set of transcription factors (TFs) for their differentiation and functions. However, similarities and differences in the induction of these TFs in related lymphocytes are still elusive. Here, we show that T helper-1 (Th1) cells and natural killer (NK) cells displayed distinct epigenomes at the Tbx21 locus, which encodes T-bet, a critical TF for regulating type 1 immune responses. The initial induction of T-bet in NK precursors was dependent on the NK-specific DNase I hypersensitive site Tbx21-CNS-3, and the expression of the interleukin-18 (IL-18) receptor; IL-18 induced T-bet expression through the transcription factor RUNX3, which bound to Tbx21-CNS-3. By contrast, signal transducer and activator of transcription (STAT)-binding motifs within Tbx21-CNS-12 were critical for IL-12-induced T-bet expression during Th1 cell differentiation both in vitro and in vivo. Thus, type 1 innate and adaptive lymphocytes utilize distinct enhancer elements for their development and differentiation.
KW - STAT proteins
KW - T helper cells
KW - cis-regulatory elements
KW - innate lymphoid cells
KW - lymphocyte development and differentiation
KW - transcription factors
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U2 - 10.1016/j.immuni.2022.03.005
DO - 10.1016/j.immuni.2022.03.005
M3 - Article
C2 - 35381213
AN - SCOPUS:85127676653
SN - 1074-7613
VL - 55
SP - 639-655.e7
JO - Immunity
JF - Immunity
IS - 4
ER -
