Genetic Distinction Between Functional Tissue-resident and Conventional Natural Killer Cells

Overview

Journal iScience

Publisher Cell Press

Date 2023 Jul 5

PMID 37404378

Authors

Luni Hu

Mengwei Han

Yichen Deng

Jingjing Gong

Zhiyuan Hou

Yanyu Zeng

Yime Zhang

Jing He

Chao Zhong

Affiliations

Soon will be listed here.

Abstract

Tissue-residential natural killer (trNK) cells act as pioneering responders during infectious challenges. However, their discrimination with conventional NK (cNK) cells is still an issue. Through an integrative transcriptome comparison of the two NK subgroups from different tissues, we have defined two genesets capable of efficiently distinguishing them. Based on the two genesets, a fundamental difference between the activation of trNK and cNK is identified and further confirmed. Mechanistically, we have discovered a particular role of chromatin landscape in regulating the trNK activation. In addition, IL-21R and IL-18R are respectively highly expressed by trNK and cNK, indicating a role of cytokine milieu in determining their differential activation. Indeed, IL-21 is particularly critical in accessorily promoting trNK activation using a bunch of bifunctional transcription factors. Together, this study sheds light on the difference between trNK and cNK, which will further expand our knowledge about their distinct functionalities during immune responses.

Citing Articles

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References

Hsu J, Sage J . Novel functions for the transcription factor E2F4 in development and disease. Cell Cycle. 2016; 15(23):3183-3190. PMC: 5176148. DOI: 10.1080/15384101.2016.1234551. View

Nixon B, Chou C, Krishna C, Dadi S, Michel A, Cornish A . Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity. Sci Immunol. 2022; 7(70):eabi8642. PMC: 9233921. DOI: 10.1126/sciimmunol.abi8642. View

Gasteiger G, Fan X, Dikiy S, Lee S, Rudensky A . Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science. 2015; 350(6263):981-5. PMC: 4720139. DOI: 10.1126/science.aac9593. View

Feng Y, Desjardins C, Cooper O, Kontor A, Nocco S, Naya F . EGR1 Functions as a Potent Repressor of MEF2 Transcriptional Activity. PLoS One. 2015; 10(5):e0127641. PMC: 4444265. DOI: 10.1371/journal.pone.0127641. View

Ducimetiere L, Lucchiari G, Litscher G, Nater M, Heeb L, Gonzalo Nunez N . Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis. Proc Natl Acad Sci U S A. 2021; 118(27). PMC: 8271692. DOI: 10.1073/pnas.2026271118. View

Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H . Repression of p15INK4b expression by Myc through association with Miz-1. Nat Cell Biol. 2001; 3(4):392-9. DOI: 10.1038/35070076. View

Kamran P, Sereti K, Zhao P, Ali S, Weissman I, Ardehali R . Parabiosis in mice: a detailed protocol. J Vis Exp. 2013; (80). PMC: 3938334. DOI: 10.3791/50556. View

Wright D, Wagers A, Gulati A, Johnson F, Weissman I . Physiological migration of hematopoietic stem and progenitor cells. Science. 2001; 294(5548):1933-6. DOI: 10.1126/science.1064081. View

Tang L, Peng H, Zhou J, Chen Y, Wei H, Sun R . Differential phenotypic and functional properties of liver-resident NK cells and mucosal ILC1s. J Autoimmun. 2015; 67:29-35. DOI: 10.1016/j.jaut.2015.09.004. View

10.

Gotthardt D, Trifinopoulos J, Sexl V, Putz E . JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation. Front Immunol. 2019; 10:2590. PMC: 6861185. DOI: 10.3389/fimmu.2019.02590. View

11.

Filipovic I, Chiossone L, Vacca P, Hamilton R, Ingegnere T, Doisne J . Molecular definition of group 1 innate lymphoid cells in the mouse uterus. Nat Commun. 2018; 9(1):4492. PMC: 6206068. DOI: 10.1038/s41467-018-06918-3. View

12.

Chen Y, Wang X, Hao X, Li B, Tao W, Zhu S . Ly49E separates liver ILC1s into embryo-derived and postnatal subsets with different functions. J Exp Med. 2022; 219(5). PMC: 8992684. DOI: 10.1084/jem.20211805. View

13.

Bai L, Vienne M, Tang L, Kerdiles Y, Etiennot M, Escaliere B . Liver type 1 innate lymphoid cells develop locally via an interferon-γ-dependent loop. Science. 2021; 371(6536). DOI: 10.1126/science.aba4177. View

14.

Peng H, Jiang X, Chen Y, Sojka D, Wei H, Gao X . Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest. 2013; 123(4):1444-56. PMC: 3613925. DOI: 10.1172/JCI66381. View

15.

Klose C, Flach M, Mohle L, Rogell L, Hoyler T, Ebert K . Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014; 157(2):340-356. DOI: 10.1016/j.cell.2014.03.030. View

16.

Yomogida K, Bigley T, Trsan T, Gilfillan S, Cella M, Yokoyama W . Hobit confers tissue-dependent programs to type 1 innate lymphoid cells. Proc Natl Acad Sci U S A. 2021; 118(50). PMC: 8685927. DOI: 10.1073/pnas.2117965118. View

17.

Shen N, Jiang S, Lu J, Yu X, Lai S, Zhang J . The constitutive activation of Egr-1/C/EBPa mediates the development of type 2 diabetes mellitus by enhancing hepatic gluconeogenesis. Am J Pathol. 2014; 185(2):513-23. DOI: 10.1016/j.ajpath.2014.10.016. View

18.

Bakovic M, Waite K, Vance D . Functional significance of Sp1, Sp2, and Sp3 transcription factors in regulation of the murine CTP:phosphocholine cytidylyltransferase alpha promoter. J Lipid Res. 2000; 41(4):583-94. View

19.

Bjorklund A, Forkel M, Picelli S, Konya V, Theorell J, Friberg D . The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016; 17(4):451-60. DOI: 10.1038/ni.3368. View

20.

Rashkovan M, Vadnais C, Ross J, Gigoux M, Suh W, Gu W . Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination. Proc Natl Acad Sci U S A. 2014; 111(50):E5411-9. PMC: 4273400. DOI: 10.1073/pnas.1412107111. View