Epigenetic control of innate and adaptive immune memory

Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. Recent work demonstrates that natural killer (NK) cells of the innate immune system also exhibit these adaptive traits during infection. Here we demonstrate that differentiating and ‘memory’ NK cells possess distinct chromatin accessibility states and that their epigenetic profiles reveal a ‘poised’ regulatory program at the memory stage. Furthermore, we elucidate how individual STAT transcription factors differentially control epigenetic and transcriptional states early during infection. Finally, concurrent chromatin profiling of the canonical CD8+ T cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining NK cells and CD8+ T cells. Overall, our study reveals the dynamic nature of epigenetic modifications during the generation of innate and adaptive lymphocyte memory.Natural killer (NK) cells can acquire ‘memory’ signatures. Sun and colleagues examine the dynamic ATAC-seq and functional RNA-seq changes observed upon generation of NK cell memory and show distinct roles for transcription factors STAT1 and STAT4.

[1]  Mark Gerstein,et al.  Global changes in STAT target selection and transcription regulation upon interferon treatments. , 2005, Genes & development.

[2]  Joseph C. Sun,et al.  Cutting Edge: Stage-Specific Requirement of IL-18 for Antiviral NK Cell Expansion , 2015, The Journal of Immunology.

[3]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[4]  Joseph C. Sun,et al.  Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses , 2017, Science Immunology.

[5]  Aaron R. Quinlan,et al.  Bioinformatics Applications Note Genome Analysis Bedtools: a Flexible Suite of Utilities for Comparing Genomic Features , 2022 .

[6]  Christina S. Leslie,et al.  Chromatin states define tumor-specific T cell dysfunction and reprogramming , 2017, Nature.

[7]  Georgios K. Georgakilas,et al.  Lineage‐Determining Transcription Factor TCF‐1 Initiates the Epigenetic Identity of T Cells , 2018, Immunity.

[8]  Charles C. Kim,et al.  Molecular definition of the identity and activation of natural killer cells , 2012, Nature Immunology.

[9]  Christine A. Biron,et al.  Interferon α/β-mediated inhibition and promotion of interferon γ: STAT1 resolves a paradox , 2000, Nature Immunology.

[10]  Björn Usadel,et al.  Trimmomatic: a flexible trimmer for Illumina sequence data , 2014, Bioinform..

[11]  M. Colonna,et al.  NK cell-activating receptors require PKC-theta for sustained signaling, transcriptional activation, and IFN-gamma secretion. , 2008, Blood.

[12]  A. Makrigiannis,et al.  Ly49h-Deficient C57BL/6 Mice: A New Mouse Cytomegalovirus-Susceptible Model Remains Resistant to Unrelated Pathogens Controlled by the NK Gene Complex1 , 2008, The Journal of Immunology.

[13]  M. Caligiuri,et al.  Innate or Adaptive Immunity? The Example of Natural Killer Cells , 2011, Science.

[14]  Joseph C. Sun,et al.  Proinflammatory cytokine signaling required for the generation of natural killer cell memory , 2012, The Journal of experimental medicine.

[15]  A. Rudensky,et al.  Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells , 2007, Nature.

[16]  M. Kaplan,et al.  Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice , 1996, Nature.

[17]  Avinash Bhandoola,et al.  TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow , 2015, Nature Immunology.

[18]  W. Yokoyama,et al.  Specific and nonspecific NK cell activation during virus infection , 2001, Nature Immunology.

[19]  S. Berger,et al.  Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade , 2016, Science.

[20]  Yuka Kanno,et al.  Mechanisms and consequences of Jak–STAT signaling in the immune system , 2017, Nature Immunology.

[21]  Todd M. Allen,et al.  The epigenetic landscape of T cell exhaustion , 2016, Science.

[22]  G. Koretzky,et al.  T cell activation. , 2009, Annual review of immunology.

[23]  Massimo Gadina,et al.  The JAK-STAT pathway: impact on human disease and therapeutic intervention. , 2015, Annual review of medicine.

[24]  David S. Lapointe,et al.  ChIPpeakAnno: a Bioconductor package to annotate ChIP-seq and ChIP-chip data , 2010, BMC Bioinformatics.

[25]  J. Aster,et al.  T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling , 2011, Proceedings of the National Academy of Sciences.

[26]  Lior Pachter,et al.  Near-optimal probabilistic RNA-seq quantification , 2016, Nature Biotechnology.

[27]  Raymond M. Welsh,et al.  Murine Cytomegalovirus Is Regulated by a Discrete Subset of Natural Killer Cells Reactive with Monoclonal Antibody to Ly49h , 2001, The Journal of experimental medicine.

[28]  J. Harty,et al.  Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1. , 2010, Immunity.

[29]  Joseph C. Sun,et al.  The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection , 2014, Nature Immunology.

[30]  M. Smyth,et al.  Functional interactions between dendritic cells and NK cells during viral infection , 2003, Nature Immunology.

[31]  John T. Chang,et al.  Epigenetic landscapes reveal transcription factors regulating CD8+ T cell differentiation , 2017, Nature Immunology.

[32]  A. Rao,et al.  Dynamic Changes in Chromatin Accessibility Occur in CD8+ T Cells Responding to Viral Infection. , 2016, Immunity.

[33]  Christine A. Biron,et al.  Type 1 Interferons and the Virus-Host Relationship: A Lesson in Détente , 2006, Science.

[34]  Joseph C. Sun,et al.  Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide , 2016, The Journal of experimental medicine.

[35]  Yuka Kanno,et al.  BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers , 2016, Nature Immunology.

[36]  D. Fremont,et al.  Recognition of a virus-encoded ligand by a natural killer cell activation receptor , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Nikhil S. Joshi,et al.  The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection , 2015, The Journal of experimental medicine.

[38]  J. O’Shea,et al.  Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. , 2012, Blood.

[39]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[40]  Howard Y. Chang,et al.  Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position , 2013, Nature Methods.

[41]  Cory Y. McLean,et al.  GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[42]  J. O’Shea,et al.  Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality , 2016, Cell.

[43]  Robert Gentleman,et al.  Software for Computing and Annotating Genomic Ranges , 2013, PLoS Comput. Biol..

[44]  Susan M. Kaech,et al.  Molecular and Functional Profiling of Memory CD8 T Cell Differentiation , 2002, Cell.

[45]  L. Bird,et al.  Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection , 2015, The Journal of experimental medicine.

[46]  M. Delorenzi,et al.  The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes. , 2017, Cell reports.

[47]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[48]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[49]  R. Schreiber,et al.  Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway , 1996, Cell.

[50]  Peter J. Bickel,et al.  Measuring reproducibility of high-throughput experiments , 2011, 1110.4705.

[51]  S. Haferkamp,et al.  LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. , 2016, Cell metabolism.

[52]  Howard Y. Chang,et al.  Lineage-specific and single cell chromatin accessibility charts human hematopoiesis and leukemia evolution , 2016, Nature Genetics.

[53]  T. Kambayashi,et al.  Cutting Edge: Murine NK Cells Degranulate and Retain Cytotoxic Function without Store-Operated Calcium Entry , 2017, The Journal of Immunology.

[54]  Christina S. Leslie,et al.  Early enhancer establishment and regulatory locus complexity shape transcriptional programs in hematopoietic differentiation , 2015, Nature Genetics.

[55]  Alejandro Chavez,et al.  A critical role for TCF-1 in T-lineage specification and differentiation , 2011, Nature.

[56]  Lewis L. Lanier,et al.  NK cell development, homeostasis and function: parallels with CD8+ T cells , 2011, Nature Reviews Immunology.

[57]  Joseph C. Sun,et al.  Adaptive Immune Features of Natural Killer Cells , 2009, Nature.

[58]  L. Lanier,et al.  Direct Recognition of Cytomegalovirus by Activating and Inhibitory NK Cell Receptors , 2002, Science.

[59]  Chen Zeng,et al.  Tcf1 and Lef1 transcription factors establish CD8+ T cell identity through intrinsic HDAC activity , 2016, Nature Immunology.

[60]  Paul G. Thomas,et al.  De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation , 2017, Cell.