Histone Deacetylases 1 and 2 Restrain CD4+ Cytotoxic T Lymphocyte Differentiation

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2020 Feb 28

PMID 32102981

Citations 15

Authors

Teresa Preglej

Patricia Hamminger

Maik Luu

Tanja Bulat

Liisa Andersen

Lisa Goschl

Valentina Stolz

Ramona Rica

Lisa Sandner

Darina Waltenberger

Roland Tschismarov

Thomas Faux

Thorina Boenke

Asta Laiho

Laura L Elo

Shinya Sakaguchi

Gunter Steiner

Thomas Decker

Barbara Bohle

Alexander Visekruna

Christoph Bock

Birgit Strobl

Christian Seiser

Nicole Boucheron

Wilfried Ellmeier

Affiliations

Soon will be listed here.

Abstract

Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1cKO-HDAC2HET) in CD4+ T cells induced a T helper cytotoxic program that was controlled by IFN-γ-JAK1/2-STAT1 signaling. In vitro, activated HDAC1cKO-HDAC2HET CD4+ T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8+ T cells and human CD4+ CTLs. In vivo, murine cytomegalovirus-infected HDAC1cKO-HDAC2HET mice displayed a stronger induction of CD4+ CTL features compared with infected WT mice. Finally, murine and human CD4+ T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4+ CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4+ CTLs.

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References

Tan J, McKenzie C, Potamitis M, Thorburn A, Mackay C, Macia L . The role of short-chain fatty acids in health and disease. Adv Immunol. 2014; 121:91-119. DOI: 10.1016/B978-0-12-800100-4.00003-9. View

Girdlestone J, Wing M . Autocrine activation by interferon-gamma of STAT factors following T cell activation. Eur J Immunol. 1996; 26(3):704-9. DOI: 10.1002/eji.1830260329. View

Reis B, Hoytema van Konijnenburg D, Grivennikov S, Mucida D . Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. Immunity. 2014; 41(2):244-56. PMC: 4287410. DOI: 10.1016/j.immuni.2014.06.017. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Haberland M, Montgomery R, Olson E . The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2008; 10(1):32-42. PMC: 3215088. DOI: 10.1038/nrg2485. View

Kernbauer E, Maier V, Stoiber D, Strobl B, Schneckenleithner C, Sexl V . Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection. PLoS Pathog. 2012; 8(6):e1002763. PMC: 3375314. DOI: 10.1371/journal.ppat.1002763. View

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S . TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013; 14(4):R36. PMC: 4053844. DOI: 10.1186/gb-2013-14-4-r36. View

Wolfer A, Bakker T, Wilson A, Nicolas M, Ioannidis V, Littman D . Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8T cell development. Nat Immunol. 2001; 2(3):235-41. DOI: 10.1038/85294. View

Patil V, Madrigal A, Schmiedel B, Clarke J, ORourke P, De Silva A . Precursors of human CD4 cytotoxic T lymphocytes identified by single-cell transcriptome analysis. Sci Immunol. 2018; 3(19). PMC: 5931334. DOI: 10.1126/sciimmunol.aan8664. View

10.

Brown D, Kamperschroer C, Dilzer A, Roberts D, Swain S . IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity in antigen specific CD4+ T cells. Cell Immunol. 2009; 257(1-2):69-79. PMC: 2683476. DOI: 10.1016/j.cellimm.2009.03.002. View

11.

Jin Y, Jeon E, Li Q, Lee Y, Choi J, Kim W . Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J Biol Chem. 2004; 279(28):29409-17. DOI: 10.1074/jbc.M313120200. View

12.

Falkenberg K, Johnstone R . Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014; 13(9):673-91. DOI: 10.1038/nrd4360. View

13.

Vacchio M, Wang L, Bouladoux N, Carpenter A, Xiong Y, Williams L . A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4+ T cells. Nat Immunol. 2014; 15(10):947-56. PMC: 4251968. DOI: 10.1038/ni.2960. View

14.

Choudhary C, Weinert B, Nishida Y, Verdin E, Mann M . The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. 2014; 15(8):536-50. DOI: 10.1038/nrm3841. View

15.

Verma S, Weiskopf D, Gupta A, McDonald B, Peters B, Sette A . Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection. J Virol. 2015; 90(2):650-8. PMC: 4702662. DOI: 10.1128/JVI.02123-15. View

16.

Grausenburger R, Bilic I, Boucheron N, Zupkovitz G, El-Housseiny L, Tschismarov R . Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J Immunol. 2010; 185(6):3489-97. PMC: 3175530. DOI: 10.4049/jimmunol.0903610. View

17.

Donnarumma T, Young G, Merkenschlager J, Eksmond U, Bongard N, Nutt S . Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus. Cell Rep. 2016; 17(6):1571-1583. PMC: 5149578. DOI: 10.1016/j.celrep.2016.10.013. View

18.

Arens R, Wang P, Sidney J, Loewendorf A, Sette A, Schoenberger S . Cutting edge: murine cytomegalovirus induces a polyfunctional CD4 T cell response. J Immunol. 2008; 180(10):6472-6. PMC: 2587066. DOI: 10.4049/jimmunol.180.10.6472. View

19.

Klampfer L, Huang J, Swaby L, Augenlicht L . Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem. 2004; 279(29):30358-68. DOI: 10.1074/jbc.M401359200. View

20.

Appay V, Zaunders J, Papagno L, Sutton J, Jaramillo A, Waters A . Characterization of CD4(+) CTLs ex vivo. J Immunol. 2002; 168(11):5954-8. DOI: 10.4049/jimmunol.168.11.5954. View