Distribution and storage of inflammatory memory in barrier tissues

Nature Reviews Immunology

Volumn 20, Issue 5, 2020, Pages 308-320

  Ordovas Montanes, Jose ^a,b,c,d,e   Beyaz, Semir ^f   Rakoff Nahoum, Seth ^a,d   Shalek, Alex K ^b,c,d,e,g  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b Massachusetts Institute of Technology   (United States)

^c MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^d BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^e HARVARD STEM CELL INSTITUTE   (United States)

^f Simons Center for Quantitative Biology   (United States)

^g HARVARD MIT DIVISION OF HEALTH SCIENCES AND TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALLERGEN; ANTIGEN; INTERLEUKIN 15; RANTES; TRANSFORMING GROWTH FACTOR BETA;

ADAPTATION; B LYMPHOCYTE; CELL LINEAGE; DENDRITIC CELL; ENVIRONMENTAL EXPOSURE; EPIGENETICS; EPITHELIUM CELL; HOMEOSTASIS; HUMAN; IMMUNOLOGICAL MEMORY; INFECTION; INFLAMMATORY DISEASE; LYMPHOCYTE PRESERVATION; LYMPHOID CELL; MACROPHAGE; MICROORGANISM; NERVE CELL; NONHUMAN; PHENOTYPIC PLASTICITY; PLASMA CELL; PRIORITY JOURNAL; REVIEW; STROMA CELL; T LYMPHOCYTE; ADAPTIVE IMMUNITY; EPITHELIUM; IMMUNOLOGY; INFLAMMATION; INNATE IMMUNITY;

ADAPTIVE IMMUNITY; B-LYMPHOCYTES; CELL LINEAGE; DENDRITIC CELLS; EPITHELIAL CELLS; EPITHELIUM; HUMANS; IMMUNITY, INNATE; IMMUNOLOGIC MEMORY; INFLAMMATION; MACROPHAGES; NEURONS; PLASMA CELLS; STROMAL CELLS; T-LYMPHOCYTES;

EID: 85084104316     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/s41577-019-0263-z     Document Type: Review

References (203)

1. Belkaid, Y. & Artis, D. Immunity at the barriers. Eur. J. Immunol. 43, 3096–3097 (2013).
2. Ordovas-Montanes, J. et al. The regulation of immunological processes by peripheral neurons in homeostasis and disease. Trends Immunol. 36, 578–604 (2015).
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).
4. Arendt, D. et al. The origin and evolution of cell types. Nat. Rev. Genet. 17, 744–757 (2016).
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.
6. Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).
7. Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).
8. Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004).
9. Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343–353 (2015).
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.
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.
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.
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).
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).
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.
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.
17. Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the third way in immunology. Nat. Immunol. 2, 997–1003 (2001).
18. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).
19. Satija, R. & Shalek, A. K. Heterogeneity in immune responses: from populations to single cells. Trends Immunol. 35, 219–229 (2014).
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).
21. Shalek, A. K. et al. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498, 236–240 (2013).
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).
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).
24. Conrath, U., Beckers, G. J., Langenbach, C. J. & Jaskiewicz, M. R. Priming for enhanced defense. Annu. Rev. Phytopathol. 53, 97–119 (2015).
25. Pradeu, T. & Du Pasquier, L. Immunological memory: what’s in a name? Immunol. Rev. 283, 7–20 (2018).
26. Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).
27. Everitt, A. R. et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519–523 (2012).
28. Cassone, A. The case for an expanded concept of trained immunity. mBio 9, e00570-18 (2018).
29. Dai, X. & Medzhitov, R. Inflammation: memory beyond immunity. Nature 550, 460–461 (2017).
30. Sun, J. C., Ugolini, S. & Vivier, E. Immunological memory within the innate immune system. EMBO J. 33, 1295–1303 (2014).
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).
32. + T cells in selected organs.
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).
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).
35. + T(RM) cells providing global skin immunity. Nature 483, 227–231 (2012).
36. Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).
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.
38. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).
39. Crowley, T., Buckley, C. D. & Clark, A. R. Stroma: the forgotten cells of innate immune memory. Clin. Exp. Immunol. 193, 24–36 (2018).
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).
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).
42. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).
43. Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).
44. + T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).
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).
46. Mackay, L. K. & Kallies, A. Transcriptional regulation of tissue-resident lymphocytes. Trends Immunol. 38, 94–103 (2017).
47. + T cells. Curr. Opin. Immunol. 51, 162–169 (2018).
48. Fan, X. & Rudensky, A. Y. Hallmarks of tissue-resident lymphocytes. Cell 164, 1198–1211 (2016).
49. Iwasaki, A., Foxman, E. F. & Molony, R. D. Early local immune defences in the respiratory tract. Nat. Rev. Immunol. 17, 7–20 (2017).
50. Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).
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).
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).
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).
54. Oh, J. E. et al. Migrant memory B cells secrete luminal antibody in the vagina. Nature 571, 122–126 (2019).
55. Landsverk, O. J. et al. Antibody-secreting plasma cells persist for decades in human intestine. J. Exp. Med. 214, 309–317 (2017).
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.
57. Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin a for mucosal colonization. Science 360, 795–800 (2018).
58. Dougan, S. K. et al. Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus. Nature 503, 406–409 (2013).
59. Hedrick, S. M. Understanding immunity through the lens of disease ecology. Trends Immunol. 38, 888–903 (2017).
60. Mora, J. R. et al. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424, 88–93 (2003).
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).
62. + tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).
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).
64. + tissue-resident memory T cells activate an alarm function in a tissue, providing protection from an unrelated pathogen.
65. Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).
66. + T cells. Nature 477, 216–219 (2011).
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 10.1101/610634 (2019).
68. + T cells in the upper respiratory tract prevent pulmonary influenza virus infection. Sci. Immunol. 2, eaam6970 (2017).
69. + T cell formation during viral infection. J. Exp. Med. 213, 951–966 (2016).
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).
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).
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).
73. + T cell subsets. Immunity 31, 811–822 (2009).
74. + T cells for tissue-resident memory fate. Science 366, eaav5728 (2019).
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).
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).
77. Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).
78. + T cells. Nature 559, 264–268 (2018).
79. RM maintenance is regulated by tissue damage via P2RX7. Sci Immunol. 3, eaau1022 (2018).
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).
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).
82. + memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat. Commun. 7, 11514 (2016).
83. + T cells inhabit the human lungs. Mucosal Immunol. 11, 654–667 (2018).
84. + tissue-resident memory T cells. Sci Immunol. 4, eaax5595 (2019).
85. + cutaneous resident memory T cells are found in the circulation of healthy individuals. Sci Immunol. 4, eaav8995 (2019).
86. + resident memory T cells dominate immunosurveillance and orchestrate local recall responses. J. Exp. Med. 216, 1214–1229 (2019).
87. DiSpirito, J. R. et al. Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci Immunol. 3, eaat5861 (2018).
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.
89. van der Veeken, J. et al. Memory of inflammation in regulatory T cells. Cell 166, 977–990 (2016).
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.
91. + resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).
92. Kotas, M. E. & Locksley, R. M. Why innate lymphoid cells? Immunity 48, 1081–1090 (2018).
93. Linehan, J. L. et al. Non-classical immunity controls microbiota impact on skin immunity and tissue repair. Cell 172, 784–796.e18 (2018).
94. Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).
95. Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).
96. Harrison, O. J. et al. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science 363, eaat6280 (2019).
97. Sheridan, B. S. et al. γδ T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 39, 184–195 (2013).
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).
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.
100. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).
101. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
102. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).
103. Monticelli, S. & Natoli, G. Short-term memory of danger signals and environmental stimuli in immune cells. Nat. Immunol. 14, 777–784 (2013).
104. Ostuni, R. & Natoli, G. Lineages, cell types and functional states: a genomic view. Curr. Opin. Cell Biol. 25, 759–764 (2013).
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.
106. Smale, S. T., Tarakhovsky, A. & Natoli, G. Chromatin contributions to the regulation of innate immunity. Annu. Rev. Immunol. 32, 489–511 (2014).
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).
108. Guilliams, M. & Scott, C. L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).
109. Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190.e19 (2018).
110. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161.e12 (2018).
111. Novakovic, B. et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368.e14 (2016).
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).
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).
114. Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).
115. Montoro, D. T. et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560, 319–324 (2018).
116. Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
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).
118. Palm, N. W., Rosenstein, R. K. & Medzhitov, R. Allergic host defences. Nature 484, 465–472 (2012).
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.
120. Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320 (2018).
121. Swamy, M., Jamora, C., Havran, W. & Hayday, A. Epithelial decision makers: in search of the ‘epimmunome’. Nat. Immunol. 11, 656–665 (2010).
122. Lau, C. M. et al. Epigenetic control of innate and adaptive immune memory. Nat. Immunol. 19, 963–972 (2018).
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).
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).
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).
126. Stewart, W. E. 2nd, Gosser, L. B. & Lockart, R. Z. Jr Priming: a nonantiviral function of interferon. J. Virol. 7, 792–801 (1971).
127. Isaacs, A. & Burke, D. C. Mode of action of interferon. Nature 182, 1073–1074 (1958).
128. Klein, K. et al. The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance. J. Autoimmun. 83, 122–133 (2017).
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).
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).
131. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).
132. Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).
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).
134. Chavan, S. S., Pavlov, V. A. & Tracey, K. J. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 46, 927–942 (2017).
135. + 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.
136. Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).
137. Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097.e22 (2018).
138. Klose, C. S. & Artis, D. Neuronal regulation of innate lymphoid cells. Curr. Opin. Immunol. 56, 94–99 (2018).
139. Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016).
140. Choi, G. B. et al. Driving opposing behaviors with ensembles of piriform neurons. Cell 146, 1004–1015 (2011).
141. Rakoff-Nahoum, S., Foster, K. R. & Comstock, L. E. The evolution of cooperation within the gut microbiota. Nature 533, 255–259 (2016).
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).
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.
144. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).
145. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).
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).
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.
148. Schneider, C. et al. A metabolite-triggered tuft cell-ILC2 circuit drives small intestinal remodeling. Cell 174, 271–284.e14 (2018).
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).
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).
151. Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129.e11 (2017).
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).
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).
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.
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).
156. Dahlgren, M. W. et al. Adventitial stromal cells define group 2 innate lymphoid cell tissue niches. Immunity 50, 707–722 (2019).
157. Denton, A. E. et al. Type I interferon induces CXCL13 to support ectopic germinal center formation. J. Exp. Med. 216, 621–637 (2019).
158. + T cells cooperate to form stable clusters in tissues.
159. + T cells during influenza viral infection. Immunity 41, 633–645 (2014).
160. + T cells. Immunity 51, 285–297.e5 (2019).
161. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).
162. Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373–377 (2018).
163. Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364, 1179–1184 (2019).
164. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).
165. Yang, Y. et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152–156 (2014).
166. Omenetti, S. et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity 51, 77–89.e6 (2019).
167. Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).
168. Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50, 432–445.e7 (2019).
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).
170. Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).
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.
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).
173. Genshaft, A. S. et al. Multiplexed, targeted profiling of single-cell proteomes and transcriptomes in a single reaction. Genome Biol. 17, 188 (2016).
174. Stoeckius, M. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865–868 (2017).
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).
176. Dekker, J. et al. The 4D nucleome project. Nature 549, 219–226 (2017).
177. Cao, J. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018).
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).
179. Goltsev, Y. et al. Deep profiling of mouse splenic architecture with CODEX multiplexed imaging. Cell 174, 968–981.e15 (2018).
180. Angelo, M. et al. Multiplexed ion beam imaging of human breast tumors. Nat. Med. 20, 436–442 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
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 10.1101/689273 (2019).
190. Huang, H. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547, 173–178 (2017).
191. Schleimer, R. P. Immunopathogenesis of chronic rhinosinusitis and nasal polyposis. Annu. Rev. Pathol. 12, 331–357 (2017).
192. Neurath, M. F. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat. Immunol. 20, 970–979 (2019).
193. Arijs, I. et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut 58, 1612–1619 (2009).
194. Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).
195. Henikoff, S. & Greally, J. M. Epigenetics, cellular memory and gene regulation. Curr. Biol. 26, R644–R648 (2016).
196. Ptashne, M. The chemistry of regulation of genes and other things. J. Biol. Chem. 289, 5417–5435 (2014).
197. Vahedi, G. et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520, 558–562 (2015).
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).
199. Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012).
200. Yosef, N. et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496, 461–468 (2013).
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).
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).
203. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes. Dev. 25, 2227–2241 (2011).