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Distribution and storage of inflammatory memory in barrier tissues

Nature Reviews Immunology volume 20, pages 308–320 (2020)Cite this article

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Abstract

Memories of previous immune events enable barrier tissues to rapidly recall distinct environmental exposures. To effectively inform future responses, these past experiences can be stored in cell types that are long-term residents or essential constituents of tissues. There is an emerging understanding that, in addition to antigen-specific immune cells, diverse haematopoietic, stromal, parenchymal and neuronal cell types can store inflammatory memory. Here, we explore the impact of previous immune activity on various cell lineages with the goal of presenting a unified view of inflammatory memory to environmental exposures (such as allergens, antigens, noxious agents and microorganisms) at barrier tissues. We propose that inflammatory memory is distributed across diverse cell types and stored through shifts in cell states, and we provide a framework to guide future experiments. This distribution and storage may promote adaptation or maladaptation in homeostatic, maintenance and disease settings — especially if the distribution of memory favours cellular cooperation during storage or recall.

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Fig. 1: Cell type residence and permanence in barrier tissues.
Fig. 2: Properties of tissue inflammatory memory storage.
Fig. 3: Inflammatory memory alters circuits in barrier tissues.
Fig. 4: Distribution and cooperation in tissue memory.

References

  1. Belkaid, Y. & Artis, D. Immunity at the barriers. Eur. J. Immunol. 43, 3096–3097 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ordovas-Montanes, J. et al. The regulation of immunological processes by peripheral neurons in homeostasis and disease. Trends Immunol. 36, 578–604 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Arendt, D. et al. The origin and evolution of cell types. Nat. Rev. Genet. 17, 744–757 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Okabe, Y. & Medzhitov, R. Tissue biology perspective on macrophages. Nat. Immunol. 17, 9–17 (2015). This Review discusses the role of macrophages in tissue biology with a focus on cell-type diversification and specialization from an evolutionary and transcriptional perspective.

    Article  CAS  Google Scholar 

  6. Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343–353 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Natoli, G. & Ostuni, R. Adaptation and memory in immune responses. Nat. Immunol. 20, 783–792 (2019). This Review discusses the important concepts of adaptation and memory, providing definitions and molecular properties for these processes.

    Article  CAS  PubMed  Google Scholar 

  11. Schneider, D. & Tate, A. T. Innate immune memory: activation of macrophage killing ability by developmental duties. Curr. Biol. 26, R503–R505 (2016). This Perspective outlines a framework through which to consider memory responses based on the relationship between stimulus levels and response levels.

    Article  CAS  PubMed  Google Scholar 

  12. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016). This Review outlines the properties of trained immunity, and the similarities to and differences from adaptive immunity.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Farber, D. L., Netea, M. G., Radbruch, A., Rajewsky, K. & Zinkernagel, R. M. Immunological memory: lessons from the past and a look to the future. Nat. Rev. Immunol. 16, 124–128 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Naik, S., Larsen, S. B., Cowley, C. J. & Fuchs, E. Two to tango: dialog between immunity and stem cells in health and disease. Cell 175, 908–920 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ordovas-Montanes, J. et al. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560, 649–654 (2018). This study demonstrates that human epithelial stem cells may contribute to the persistence of disease by serving as repositories for allergic inflammatory memories.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Naik, S. et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017). This study identifies a prolonged memory to acute inflammation that allows murine epidermal stem cells to repair wounds more rapidly on subsequent damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the third way in immunology. Nat. Immunol. 2, 997–1003 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Satija, R. & Shalek, A. K. Heterogeneity in immune responses: from populations to single cells. Trends Immunol. 35, 219–229 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gierahn, T. M. et al. Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput. Nat. Methods 14, 395–398 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shalek, A. K. et al. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498, 236–240 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Prakadan, S. M., Shalek, A. K. & Weitz, D. A. Scaling by shrinking: empowering single-cell ‘omics’ with microfluidic devices. Nat. Rev. Genet. 18, 345–361 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nunez, J. K., Bai, L., Harrington, L. B., Hinder, T. L. & Doudna, J. A. CRISPR immunological memory requires a host factor for specificity. Mol. Cell 62, 824–833 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Conrath, U., Beckers, G. J., Langenbach, C. J. & Jaskiewicz, M. R. Priming for enhanced defense. Annu. Rev. Phytopathol. 53, 97–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Pradeu, T. & Du Pasquier, L. Immunological memory: what’s in a name? Immunol. Rev. 283, 7–20 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Everitt, A. R. et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519–523 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cassone, A. The case for an expanded concept of trained immunity. mBio 9, e00570-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dai, X. & Medzhitov, R. Inflammation: memory beyond immunity. Nature 550, 460–461 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Sun, J. C., Ugolini, S. & Vivier, E. Immunological memory within the innate immune system. EMBO J. 33, 1295–1303 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. von Andrian, U. H. & Mackay, C. R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

    Article  Google Scholar 

  32. Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015). This study finds that tissue dissociation techniques underestimate cellular recovery, and quantifies the ratio of parenchymal to tissue-resident CD8 + T cells in selected organs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510–5514 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Jiang, X. et al. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 483, 227–231 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhou, X. et al. Circuit design features of a stable two-cell system. Cell 172, 744–757.e17 (2018). This study uses computational predictions and experiments to identify the features of macrophage–fibroblast circuits based on growth factor exchange.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Crowley, T., Buckley, C. D. & Clark, A. R. Stroma: the forgotten cells of innate immune memory. Clin. Exp. Immunol. 193, 24–36 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sohn, C. et al. Prolonged tumor necrosis factor α primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol. 67, 86–95 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wolff, B., Burns, A. R., Middleton, J. & Rot, A. Endothelial cell “memory” of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies. J. Exp. Med. 188, 1757–1762 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Cheroutre, H. & Madakamutil, L. Acquired and natural memory T cells join forces at the mucosal front line. Nat. Rev. Immunol. 4, 290–300 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Mackay, L. K. & Kallies, A. Transcriptional regulation of tissue-resident lymphocytes. Trends Immunol. 38, 94–103 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Milner, J. J. & Goldrath, A. W. Transcriptional programming of tissue-resident memory CD8+ T cells. Curr. Opin. Immunol. 51, 162–169 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fan, X. & Rudensky, A. Y. Hallmarks of tissue-resident lymphocytes. Cell 164, 1198–1211 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Iwasaki, A., Foxman, E. F. & Molony, R. D. Early local immune defences in the respiratory tract. Nat. Rev. Immunol. 17, 7–20 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Onodera, T. et al. Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection. Proc. Natl Acad. Sci. USA 109, 2485–2490 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Adachi, Y. et al. Distinct germinal center selection at local sites shapes memory B cell response to viral escape. J. Exp. Med. 212, 1709–1723 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Allie, S. R. et al. The establishment of resident memory B cells in the lung requires local antigen encounter. Nat. Immunol. 20, 97–108 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Oh, J. E. et al. Migrant memory B cells secrete luminal antibody in the vagina. Nature 571, 122–126 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Landsverk, O. J. et al. Antibody-secreting plasma cells persist for decades in human intestine. J. Exp. Med. 214, 309–317 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Foster, K. R., Schluter, J., Coyte, K. Z. & Rakoff-Nahoum, S. The evolution of the host microbiome as an ecosystem on a leash. Nature 548, 43–51 (2017). This Perspective provides an evolutionarily-based framework to understand host–microorganism interactions with an emphasis on studying the axes of microbial competition and host control.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin a for mucosal colonization. Science 360, 795–800 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dougan, S. K. et al. Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus. Nature 503, 406–409 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hedrick, S. M. Understanding immunity through the lens of disease ecology. Trends Immunol. 38, 888–903 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mora, J. R. et al. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424, 88–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Schenkel, J. M. et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ariotti, S. et al. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014). Together with Schenkel et al. (2014), this study reports how CD8 + tissue-resident memory T cells activate an alarm function in a tissue, providing protection from an unrelated pathogen.

    Article  CAS  PubMed  Google Scholar 

  65. Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Roychoudhury, P. et al. Elimination of HSV-2 infected cells is mediated predominantly by paracrine effects of tissue-resident T cell derived cytokines. Preprint at bioRxiv https://doi.org/10.1101/610634 (2019).

    Article  Google Scholar 

  68. Pizzolla, A. et al. Resident memory CD8+ T cells in the upper respiratory tract prevent pulmonary influenza virus infection. Sci. Immunol. 2, eaam6970 (2017).

    Article  PubMed  Google Scholar 

  69. Khan, T. N., Mooster, J. L., Kilgore, A. M., Osborn, J. F. & Nolz, J. C. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. J. Exp. Med. 213, 951–966 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Casey, K. A. et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 4866–4875 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037–7042 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mackay, L. K. et al. T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate. Immunity 43, 1101–1111 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Mortier, E. et al. Macrophage- and dendritic-cell-derived interleukin-15 receptor α supports homeostasis of distinct CD8+ T cell subsets. Immunity 31, 811–822 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Mani, V. et al. Migratory DCs activate TGF-β to precondition naive CD8+ T cells for tissue-resident memory fate. Science 366, eaav5728 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Turner, D. L. et al. Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal. Immunol. 7, 501–510 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Turner, D. L. et al. Biased generation and in situ activation of lung tissue-resident memory CD4 T cells in the pathogenesis of allergic asthma. J. Immunol. 200, 1561–1569 (2018).

    CAS  PubMed  Google Scholar 

  77. Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Borges da Silva, H. et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559, 264–268 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Stark, R. et al. TRM maintenance is regulated by tissue damage via P2RX7. Sci Immunol. 3, eaau1022 (2018).

    Article  PubMed  Google Scholar 

  80. Kumar, B. V. et al. Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites. Cell Rep. 20, 2921–2934 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl Med. 4, 117ra117 (2012).

    Article  CAS  Google Scholar 

  82. Collins, N. et al. Skin CD4+ memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat. Commun. 7, 11514 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Oja, A. E. et al. Trigger-happy resident memory CD4+ T cells inhabit the human lungs. Mucosal Immunol. 11, 654–667 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Carbone, F. R. & Gebhardt, T. Should I stay or should I go—reconciling clashing perspectives on CD4+ tissue-resident memory T cells. Sci Immunol. 4, eaax5595 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Klicznik, M. M. et al. Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy individuals. Sci Immunol. 4, eaav8995 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Beura, L. K. et al. CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses. J. Exp. Med. 216, 1214–1229 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. DiSpirito, J. R. et al. Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci Immunol. 3, eaat5861 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Rosenblum, M. D. et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538–542 (2011). This study uses tissue-specific autoantigen expression to identify that regulatory T cells are maintained in tissues and provide enhanced suppression to subsequent autoimmune reactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. van der Veeken, J. et al. Memory of inflammation in regulatory T cells. Cell 166, 977–990 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Kadoki, M. et al. Organism-level analysis of vaccination reveals networks of protection across tissues. Cell 171, 398–413.e21 (2017). This study provides a characterization of intra-tissue networks of communication after vaccination and viral infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Beura, L. K. et al. Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kotas, M. E. & Locksley, R. M. Why innate lymphoid cells? Immunity 48, 1081–1090 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Linehan, J. L. et al. Non-classical immunity controls microbiota impact on skin immunity and tissue repair. Cell 172, 784–796.e18 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Harrison, O. J. et al. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science 363, eaat6280 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Sheridan, B. S. et al. γδ T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 39, 184–195 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Martinez-Gonzalez, I. et al. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation. Immunity 45, 198–208 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014). This study illustrates how diet can shift barrier tissues between type 17 and type 2 immunity based on the state of tissue-resident ILCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Monticelli, S. & Natoli, G. Short-term memory of danger signals and environmental stimuli in immune cells. Nat. Immunol. 14, 777–784 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Ostuni, R. & Natoli, G. Lineages, cell types and functional states: a genomic view. Curr. Opin. Cell Biol. 25, 759–764 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013). This study identifies latent enhancers in macrophages as regions of the genome in terminally differentiated cells that acquire enhancer-like characteristics after initial stimulation.

    Article  CAS  PubMed  Google Scholar 

  106. Smale, S. T., Tarakhovsky, A. & Natoli, G. Chromatin contributions to the regulation of innate immunity. Annu. Rev. Immunol. 32, 489–511 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Yao, Y. et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175, 1634–1650.e17 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. Guilliams, M. & Scott, C. L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).

    Article  CAS  PubMed  Google Scholar 

  109. Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190.e19 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161.e12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Novakovic, B. et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368.e14 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Daniel, B. et al. The nuclear receptor PPARγ controls progressive macrophage polarization as a ligand-insensitive epigenomic ratchet of transcriptional memory. Immunity 49, 615–626.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hogan, B. L. et al. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15, 123–138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Montoro, D. T. et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560, 319–324 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Clevers, H., Loh, K. M. & Nusse, R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science 346, 1248012 (2014).

    Article  PubMed  CAS  Google Scholar 

  118. Palm, N. W., Rosenstein, R. K. & Medzhitov, R. Allergic host defences. Nature 484, 465–472 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016). This study illustrates how high-fat diet can alter the intrinsic properties of intestinal epithelial stem and progenitor cells, enhancing stemness and tumorigenic potential.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Swamy, M., Jamora, C., Havran, W. & Hayday, A. Epithelial decision makers: in search of the ‘epimmunome’. Nat. Immunol. 11, 656–665 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lau, C. M. et al. Epigenetic control of innate and adaptive immune memory. Nat. Immunol. 19, 963–972 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Fanucchi, S. et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat. Genet. 51, 138–150 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Powell, D. W., Pinchuk, I. V., Saada, J. I., Chen, X. & Mifflin, R. C. Mesenchymal cells of the intestinal lamina propria. Annu. Rev. Physiol. 73, 213–237 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gieseck, R. L. 3rd, Wilson, M. S. & Wynn, T. A. Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol. 18, 62–76 (2017).

    Article  PubMed  CAS  Google Scholar 

  126. Stewart, W. E. 2nd, Gosser, L. B. & Lockart, R. Z. Jr Priming: a nonantiviral function of interferon. J. Virol. 7, 792–801 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Isaacs, A. & Burke, D. C. Mode of action of interferon. Nature 182, 1073–1074 (1958).

    Article  CAS  PubMed  Google Scholar 

  128. Klein, K. et al. The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance. J. Autoimmun. 83, 122–133 (2017).

    Article  CAS  PubMed  Google Scholar 

  129. Crowley, T. et al. Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts. Arthritis Res. Ther. 19, 35 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Koch, S. R., Lamb, F. S., Hellman, J., Sherwood, E. R. & Stark, R. J. Potentiation and tolerance of Toll-like receptor priming in human endothelial cells. Transl. Res. 180, 53–67.e4 (2017).

    Article  CAS  PubMed  Google Scholar 

  131. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Godinho-Silva, C., Cardoso, F. & Veiga-Fernandes, H. Neuro-immune cell units: a new paradigm in physiology. Annu. Rev. Immunol. 37, 19–46 (2018).

    Article  PubMed  CAS  Google Scholar 

  134. Chavan, S. S., Pavlov, V. A. & Tracey, K. J. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 46, 927–942 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cohen, J. A. et al. Cutaneous TRPV1+ neurons trigger protective innate type 17 anticipatory immunity. Cell 178, 919–932 (2019). This study uses optogenetic activation of heat-sensing sensory neurons to activate an anticipatory type 17 immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097.e22 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Klose, C. S. & Artis, D. Neuronal regulation of innate lymphoid cells. Curr. Opin. Immunol. 56, 94–99 (2018).

    Article  PubMed  CAS  Google Scholar 

  139. Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Choi, G. B. et al. Driving opposing behaviors with ensembles of piriform neurons. Cell 146, 1004–1015 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rakoff-Nahoum, S., Foster, K. R. & Comstock, L. E. The evolution of cooperation within the gut microbiota. Nature 533, 255–259 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Byers, D. E. et al. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J. Clin. Invest. 123, 3967–3982 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015). This study shows that IL-22 can act directly on intestinal stem cells, illustrating a role for tissue-resident lymphocytes in providing niche signals to epithelial stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Scott, H., Solheim, B. G., Brandtzaeg, P. & Thorsby, E. HLA-DR-like antigens in the epithelium of the human small intestine. Scand. J. Immunol. 12, 77–82 (1980).

    Article  CAS  PubMed  Google Scholar 

  147. von Moltke, J., Ji, M., Liang, H. E. & Locksley, R. M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225 (2016). This study identifies tuft cells as key producers of IL-25, and also describes a proto-typical immune cell–epithelial cell circuit in type 2 immunity.

    Article  CAS  Google Scholar 

  148. Schneider, C. et al. A metabolite-triggered tuft cell-ILC2 circuit drives small intestinal remodeling. Cell 174, 271–284.e14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Nadjsombati, M. S. et al. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. Immunity 49, 33–41.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Adachi, T. et al. Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nat. Med. 21, 1272–1279 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Nagao, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat. Immunol. 13, 744–752 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl. Acad. Sci. USA 111, 5307–5312 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mayassi, T. et al. Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease. Cell 176, 967–981.e19 (2019). This study shows how, in coeliac disease, inflammation can deplete innate-like intraepithelial lymphocytes, allowing for accumulation of gluten-reactive cells and an inability to reconstitute the developmentally produced subset.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. Dahlgren, M. W. et al. Adventitial stromal cells define group 2 innate lymphoid cell tissue niches. Immunity 50, 707–722 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Denton, A. E. et al. Type I interferon induces CXCL13 to support ectopic germinal center formation. J. Exp. Med. 216, 621–637 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Iijima, N. & Iwasaki, A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 93–98 (2014). This study identifies how macrophages and tissue-resident memory CD4 + T cells cooperate to form stable clusters in tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Laidlaw, B. J. et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 51, 285–297.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  161. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    Article  CAS  PubMed  Google Scholar 

  162. Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373–377 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364, 1179–1184 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yang, Y. et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152–156 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Omenetti, S. et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity 51, 77–89.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50, 432–445.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Campbell, C. et al. Extrathymically generated regulatory T cells establish a niche for intestinal border-dwelling bacteria and affect physiologic metabolite balance. Immunity 48, 1245–1257.e9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

    Article  CAS  PubMed  Google Scholar 

  171. Lingwood, D. et al. Structural and genetic basis for development of broadly neutralizing influenza antibodies. Nature 489, 566–570 (2012). This study identifies a ‘pattern-recognition’ function for specific immunoglobulin genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Melandri, D. et al. The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. Nat. Immunol. 19, 1352–1365 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Genshaft, A. S. et al. Multiplexed, targeted profiling of single-cell proteomes and transcriptomes in a single reaction. Genome Biol. 17, 188 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Stoeckius, M. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865–868 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Shema, E., Bernstein, B. E. & Buenrostro, J. D. Single-cell and single-molecule epigenomics to uncover genome regulation at unprecedented resolution. Nat. Genet. 51, 19–25 (2019).

    Article  CAS  PubMed  Google Scholar 

  176. Dekker, J. et al. The 4D nucleome project. Nature 549, 219–226 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Cao, J. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Gerner, M. Y., Kastenmuller, W., Ifrim, I., Kabat, J. & Germain, R. N. Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity 37, 364–376 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Goltsev, Y. et al. Deep profiling of mouse splenic architecture with CODEX multiplexed imaging. Cell 174, 968–981.e15 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Angelo, M. et al. Multiplexed ion beam imaging of human breast tumors. Nat. Med. 20, 436–442 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chen, K. H., Boettiger, A. N., Moffitt, J. R., Wang, S. & Zhuang, X. RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 348, aaa6090 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Lin, J. R., Fallahi-Sichani, M. & Sorger, P. K. Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method. Nat. Commun. 6, 8390 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Baron, C. S. & van Oudenaarden, A. Unravelling cellular relationships during development and regeneration using genetic lineage tracing. Nat. Rev. Mol. Cell Biol. 20, 753–765 (2019).

    Article  CAS  PubMed  Google Scholar 

  184. Adamson, B. et al. A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response. Cell 167, 1867–1882.e21 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Dixit, A. et al. Perturb-seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens. Cell 167, 1853–1866.e17 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Rubin, A. J. et al. Coupled single-cell CRISPR screening and epigenomic profiling reveals causal gene regulatory networks. Cell 176, 361–376.e17 (2019).

    Article  CAS  PubMed  Google Scholar 

  187. Seder, R. A., Darrah, P. A. & Roederer, M. T-cell quality in memory and protection: implications for vaccine design. Nat. Rev. Immunol. 8, 247–258 (2008).

    Article  CAS  PubMed  Google Scholar 

  188. Martin-Gayo, E. et al. A reproducibility-based computational framework identifies an inducible, enhanced antiviral state in dendritic cells from HIV-1 elite controllers. Genome Biol. 19, 10 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Hughes, T. K. et al. Highly efficient, massively-parallel single-cell RNA-seq reveals cellular states and molecular features of human skin pathology. Preprint at bioRxiv https://doi.org/10.1101/689273 (2019).

    Article  Google Scholar 

  190. Huang, H. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547, 173–178 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Schleimer, R. P. Immunopathogenesis of chronic rhinosinusitis and nasal polyposis. Annu. Rev. Pathol. 12, 331–357 (2017).

    Article  CAS  PubMed  Google Scholar 

  192. Neurath, M. F. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat. Immunol. 20, 970–979 (2019).

    Article  CAS  PubMed  Google Scholar 

  193. Arijs, I. et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut 58, 1612–1619 (2009).

    Article  CAS  PubMed  Google Scholar 

  194. Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Henikoff, S. & Greally, J. M. Epigenetics, cellular memory and gene regulation. Curr. Biol. 26, R644–R648 (2016).

    Article  CAS  PubMed  Google Scholar 

  196. Ptashne, M. The chemistry of regulation of genes and other things. J. Biol. Chem. 289, 5417–5435 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Vahedi, G. et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520, 558–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Yosef, N. et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496, 461–468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Beyaz, S. et al. The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nat. Immunol. 18, 184–195 (2017).

    Article  CAS  PubMed  Google Scholar 

  203. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes. Dev. 25, 2227–2241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the following individuals for insightful discussions and comments: S. Nyquist, M. Vukovic, S. Kazer, M. Ramseier, V. Miao, C. Kummerlowe, S. Prakadan, E. Christian, A. Hornick, members of the Shalek laboratory, U. von Andrian, C. Borges, Z. Sullivan, V. Mani and S. Naik. This work was supported, in part, by the Damon Runyon Cancer Research Foundation (Howard Hughes Medical Institute Fellow DRG-2274-16; to J.O.-M.), the Richard and Susan Smith Family Foundation (to J.O.-M.), the Searle Scholars Program (to A.K.S.), the Beckman Young Investigator Program (to A.K.S.), the Pew–Stewart Scholars Program for Cancer Research (to A.K.S.), a Sloan Fellowship in Chemistry (to A.K.S.), the US National Institutes of Health (1DP2GM119419, 2U19AI089992, 2R01HL095791, 1U54CA217377, 2P01AI039671, 5U24AI118672, 2RM1HG006193, 1U2CCA23319501, 1R01AI138546, 1R01HL134539 and 1R01DA046277; to A.K.S.), the US Food and Drug Administration (HHSF223201810172C; to A.K.S.) and the Bill and Melinda Gates Foundation (to A.K.S.).

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Authors and Affiliations

  1. Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, USA

    Jose Ordovas-Montanes & Seth Rakoff-Nahoum

  2. Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA

    Jose Ordovas-Montanes & Alex K. Shalek

  3. Department of Chemistry, MIT, Cambridge, MA, USA

    Jose Ordovas-Montanes & Alex K. Shalek

  4. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA

    Jose Ordovas-Montanes & Alex K. Shalek

  5. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jose Ordovas-Montanes, Seth Rakoff-Nahoum & Alex K. Shalek

  6. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

    Jose Ordovas-Montanes & Alex K. Shalek

  7. Harvard Stem Cell Institute, Cambridge, MA, USA

    Jose Ordovas-Montanes & Alex K. Shalek

  8. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Semir Beyaz

  9. Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA

    Seth Rakoff-Nahoum

  10. Harvard–MIT Division of Health Sciences & Technology, Cambridge, MA, USA

    Alex K. Shalek

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Contributions

J.O.-M. contributed to researching the data for the article, discussion of content, and writing and editing the manuscript before submission. A.K.S. contributed to discussion of content, and writing and editing the manuscript before submission. S.B. and S.R.-N. contributed to discussion of content and editing of the manuscript before submission.

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Correspondence to Jose Ordovas-Montanes.

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A.K.S. has received compensation for consulting and SAB membership from Honeycomb Biotechnologies, Cellarity, Cogen Therapeutics and Dahlia Biosciences. All other authors declare no competing interests.

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Nature Reviews Immunology thanks A. Iwasaki, G. Natoli, M. Netea and D. Masopust for their contribution to the peer review of this work.

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Glossary

Barrier tissues

Epithelial tissues that interface directly with the external environment (that is, any surface directly and constantly exposed to the world outside the host), composed of a monolayer, pseudo-stratified or stratified epithelium, as well as an underlying stromal-derived component and other transient, resident or permanent resident cell lineages.

Immune event

Exposure to an environmental stimulus (such as allergens, antigens, noxious agents, diet, pathogens and microbial communities) or a host-derived stimulus (such as metastasis or sterile tissue damage) at a barrier tissue sensed by the host, triggering downstream transcription and/or epigenetic changes in cell state and/or cell composition in the tissue.

Memory

The properties of memory include an altered baseline, sensitivity, rapidity or maximum for a defined response upon secondary challenge to an initiating trigger.

Adaptive immune memory

Classically defined as a memory response by a cell that is considered part of the adaptive immune system (for example, T cells and B cells), based on the ability of its receptor to be formed through the recombination of genetic elements and stably inherited across cell divisions.

Cell types

Developmentally specified cell identity modules that are typically irreversible beyond enforced overexpression of lineage-overriding transcription factors.

Cell subsets

Typically developmentally stable cells, but their programming may be overridden based on niche availability or extreme environments.

Cell state

Characteristics that can be transiently acquired from tissue entry and/or an immune event, are distinct from cellular differentiation and are related to the quality (that is, type of inflammation) of an immune response.

Gene modules

Sets of co-varying genes that may be co-regulated through the activity of one or more transcription factors, or a complex thereof, often associated with a specific cell attribute such as cell type (T cell) or cell state (forkhead box P3 (FOXP3)+ regulatory T cell).

Inflammatory memory

A memory response by any cell lineage to an environmental or host-derived cue, typically acquired during an immune event.

Protective immunological memory

A functionally defensive memory response that enables the host to better respond to secondary challenge after an initial exposure. This function can comprise any of the potential mechanisms that may mediate protective recall, and these same mechanisms may concomitantly or separately mediate immunopathology.

Innate immune memory

Classically defined as a memory response by a cell that is considered part of the innate immune system (for example, macrophages and natural killer cells). However, we favour the use of innate immune memory for memory events triggered by germline-encoded receptors expressed by any cell lineage.

Lipopolysaccharide (LPS) tolerance

Macrophages exposed to sustained stimulation with LPS or high-dose LPS acquire a hypo-responsive state in which sets of inflammatory genes are blunted in their secondary response to LPS or other inflammatory cytokines.

Tuft cells

Rare chemosensory epithelial cells with a ‘tuft-like’ brush of microvilli present in epithelial (primarily mucosal) tissues of mammals, characterized by expression of taste receptors and production of instructive allergic inflammatory cytokines.

Dendritic epidermal T cells

γδ T cell receptor-expressing cells selectively localized in the epidermis that have been identified in rodents and cattle, but not in humans. In mice, essentially all dendritic epidermal T cells express the same T cell receptor constituting a prototypical innate-like T cell.

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Ordovas-Montanes, J., Beyaz, S., Rakoff-Nahoum, S. et al. Distribution and storage of inflammatory memory in barrier tissues. Nat Rev Immunol 20, 308–320 (2020). https://doi.org/10.1038/s41577-019-0263-z

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