Trained Immunity and Local Innate Immune Memory in the Lung

more frequent intervals to observe these processes and determine when and how cells are eliminated. Salzer et al.’s interesting observation that calorie restriction helps to prevent transcriptional noise and maintain cellular identity of aging papillary fibroblasts raises the question of whether a low-calorie diet can also maintain cellular density of the papillary dermis and prevent the appearance of ‘‘holes’’ within the tissue. Given the acquisition of a pro-adipogenic transcriptional profile in aged papillary fibroblasts, it will also be interesting to test whether this trait is reversed by genetic deletion or pharmacological inhibition of PPARg. If so, topical treatment with PPARg inhibitors could be an attractive method to prevent some aspects of dermal aging. Finally, the precise mechanisms by which a low-calorie diet influences dermal fibroblast identity are unclear. As caloric restriction is known to prevent certain aging-related phenotypes in epidermal stem cells (Solanas et al., 2017), some features of retarded dermal aging in calorie-restricted mice could be due to maintenance of youthful epithelial signals, while others could be facilitated by reduced systemic inflammation and/or prevention of local metabolic changes.

Unravelling these complex effects in the context of the whole organism will be a fruitful area for future investigation. In summary, these two innovative studies explore the fascinating and clinically relevant subject of fibroblast aging in vivo. The skin provides a remarkably accessible and easily manipulatable system to address these questions. It is likely that many of the paradigms established here will be applicable to understanding aging mechanisms in other stromal tissues. REFERENCES Cummings, N.E., and Lamming, D.W. (2017). Regulation of metabolic health and aging by nutrient-sensitive signaling pathways. Mol. Cell. Endocrinol. 455, 13–22. Demaria, M., Desprez, P.Y., Campisi, J., and Velarde, M.C. (2015). Cell Autonomous and NonAutonomous Effects of Senescent Cells in the Skin. J. Invest. Dermatol. 135, 1722–1726. Driskell, R.R., Lichtenberger, B.M., Hoste, E., Kretzschmar, K., Simons, B.D., Charalambous, M., Ferron, S.R., Herault, Y., Pavlovic, G., Ferguson-Smith, A.C., and Watt, F.M. (2013). Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281. Lefterova, M.I., Haakonsson, A.K., Lazar, M.A., and Mandrup, S. (2014). PPARg and the global

map of adipogenesis and beyond. Trends Endocrinol. Metab. 25, 293–302. Marsh, E., Gonzalez, D.G., Lathrop, E.A., Boucher, J., and Greco, V. (2018). Positional Stability and Membrane Occupancy Define Skin Fibroblast Homeostasis In Vivo. Cell 175, this issue, 1620–1633. Millar, S.E. (2018). Hox in the Niche Controls Hairygeneity. Cell Stem Cell 23, 457–458. Rinn, J.L., Wang, J.K., Allen, N., Brugmann, S.A., Mikels, A.J., Liu, H., Ridky, T.W., Stadler, H.S., Nusse, R., Helms, J.A., and Chang, H.Y. (2008). A dermal HOX transcriptional program regulates site-specific epidermal fate. Genes Dev. 22, 303–307. Salzer, M.C., Lafzi, A., Berenguer-Llergo, A., Youssif, C., Castellanos, A., Solanas, G., Peixoto, F.O., Stephan-Otto Attolini, C., Prats, N., Aguilera, M., et al. (2018). Identity Noise and Adipogenic Traits Characterize Dermal Fibroblast Aging. Cell 175, this issue, 1575–1590. Solanas, G., Peixoto, F.O., Perdiguero, E., Jardi, M., Ruiz-Bonilla, V., Datta, D., Symeonidi, A., Castellanos, A., Welz, P.S., Caballero, J.M., et al. (2017). Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress. Cell 170, 678–692. Yu, Z., Jiang, K., Xu, Z., Huang, H., Qian, N., Lu, Z., Chen, D., Di, R., Yuan, T., Du, Z., et al. (2018). Hoxc-Dependent Mesenchymal Niche Heterogeneity Drives Regional Hair Follicle Regeneration. Cell Stem Cell 23, 487–500.

Trained Immunity and Local Innate Immune Memory in the Lung Mihai G. Netea1,2,* and Leo A.B. Joosten1 1Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands 2Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany *Correspondence: [email protected] https://doi.org/10.1016/j.cell.2018.11.007

Trained innate immunity mediates protection against heterologous infections and is mediated by epigenetic and functional reprogramming of myeloid cells and their progenitors. Now, Yao et al. describe trained immunity induced locally in alveolar macrophages by a viral infection, with IFNg release from effector CD8+ lymphocytes initiating this process. Host immune responses are classically divided into innate and adaptive immune responses, with the latter displaying anti-

gen-specific immunological memory after an infection or vaccination. However, a growing body of evidence in recent years

argues that innate immune responses also exhibit adaptive characteristics, a de facto innate immune memory that has

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Figure 1. Systemic and Peripheral Induction of Trained Immunity Trained immunity (innate immune memory) is induced either centrally in the bone marrow influencing the functional program of immune cell progenitors and circulating innate immune cells or in the periphery in the tissues at the level of macrophages and possibly other innate immune cell populations. Induction of trained immunity in tissue macrophages can follow a canonical pathway through monocyte-derived macrophages from the circulation and a non-canonical pathway through reverse adaptive-to-innate mechanisms involving CD8+ lymphocytes-derived release of IFNg and induction of autonomous trained macrophages.

been termed ‘‘trained immunity’’ (Netea et al., 2016). Trained immunity is mediated by epigenetic, metabolic, and functional reprogramming of innate immune cells, such as myeloid cells and NK cells (Netea et al., 2016), and is systemically induced at the level of bone marrow progenitors (Kaufmann et al., 2018; Mitroulis et al., 2018). Very little was previously known, however, about whether trained immunity can be also induced in tissues or at the level of the mucosal immune system. Now, Yao and colleagues demonstrate that alveolar macrophages develop a trained immunity phenotype after a viral infection (Yao et al., 2018, this issue of Cell), showing peripheral induction of innate immune memory in the mucosal tissues for the first time. Interestingly, adaptive immune cells such as effector CD8+ lymphocytes are necessary for the initiation this process, unravelling an adaptiveto-immune reverse signaling for the induction of trained immunity (Yao et al., 2018). Important clues that innate immunity has adaptive characteristics have previ-

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ously been reported in plants and invertebrates but also in experimental studies in mice (Netea et al., 2016). Innate immune memory is also induced by vaccination of animals with bacillus Calmette Guerin (BCG), the tuberculosis vaccine, that results in heterologous protection against secondary infections with Candida albicans, Schistosoma mansoni, or influenza virus. These experimental studies have been complemented with studies showing that BCG vaccination in human volunteers protects against an experimental infection with yellow fever vaccine virus (Arts et al., 2018), while large epidemiological studies have reported protective heterologous effects for BCG, measles, and oral polio virus vaccinations (Benn et al., 2013). The main cell populations that have been reported to be responsible for innate immune memory are myeloid cells such as the monocytes and innate lymphoid cells such as natural killer (NK) cells. Given that monocytes are short-lived in the circulation, recent studies have focused on

demonstrating that trained immunity is mediated by epigenetic and transcriptional reprogramming of myeloid bone marrow progenitors (Kaufmann et al., 2018; Mitroulis et al., 2018). While these studies elucidated the mechanisms that mediate the induction of systemic trained immunity, it is likely that training of innate immune cells also takes place at a mucosal level, where long-lived tissue macrophages can insure a memory phenotype independently of monocytes and bone marrow progenitors. This hypothesis is now elegantly demonstrated by Yao et al., who report the induction of autonomous alveolar macrophages with a trained immunity phenotype after a respiratory viral infection. These trained alveolar macrophages display classic properties of trained immunity such as a defense-ready signature, high rates of glycolysis, and increased release of chemokines upon restimulation (Yao et al., 2018). Importantly, the induction of trained alveolar macrophages results in a robust host defense against a heterologous bacterial infection.

While earlier studies investigating the effect of two unrelated subsequent viral infections—lymphocytic choriomeningitis virus (LCMV) and influenza A virus—also suggested the ability to alter a secondary innate immune response at the respiratory mucosa level through induction of innate immune training (Mehta et al., 2015), the current study of Yao et al. (2018) is the first to comprehensively describe the mechanisms responsible for these protective effects. One interesting finding of Yao et al. (2018) is the observation that effector CD8+ lymphocytes are important for the initiation, but not maintenance, of the trained immunity phenotype in alveolar macrophages after this model of adenoviral infection. This effect is mediated through the release of IFNg production, and this finding is supported by a recent study showing that IFNg can induce a trained immunity phenotype (Kamada et al., 2018). The strong links between the innate and adaptive immune processes are well known, but they have always implied an innate-to-adaptive immunity direction through the stimulatory effects of antigen-presenting cells on lymphocyte activation. Although it remains to be demonstrated whether this is a more general pathway of trained immunity induction in the mucosa by various infections or whether this is specific to this type of adenoviral infection, the identification of a reverse adaptive-to-innate effect to induce innate immune memory through signals released by effector lymphocytes is a novel and exciting finding. This study establishes a new paradigm on the induction of immune memory by showing that effector CD8+ lymphocytes can induce trained immunity in mucosal-associated macrophages. Taken together, the earlier studies and the findings of Yao et al. (2018) represent evidence for a new concept in which innate immune memory is induced in vivo in two main compartments: centrally in the bone marrow influencing the functional program of immune cell progenitors and circulating innate immune cells and in

the peripheral tissues at the level of macrophages and possibly other innate immune cell populations (Figure 1). This concept is supported by the recent study reporting the induction of innate immune memory in microglia after systemic inflammation, a process which contributes to neuroinflammation in experimental models (Wendeln et al., 2018). In addition, other studies suggest that trained macrophages in the tissues may be also induced in a monocyte-dependent, T-cell-independent fashion (Machiels et al., 2017), and one may consider this a more ‘‘canonical’’ mechanism of induction of trained immunity. All in all, it is therefore likely that the history of previous inflammation or infection can be recorded both at the central (bone marrow) and local (tissue) level. While describing induction of trained immunity in the lung for the first time, the study of Yao et al. (2018) also opens the door for many more questions. Is the induction of trained immunity a general process taking place in most, if not all, tissues after insults? What is the spectrum of innate immune cells that can develop a trained immunity phenotype? Is this process different between the lung mucosa and other organs such as the gut or urinary tract? Finally, it will be crucial to investigate how trained immunity is regulated to provide enhanced host defense but at the same time counteract the development of deleterious runaway inflammation. The answers to these questions in future studies are crucial to fully understand trained immunity as a biological process and thus making it possible to target this process for diagnostic and therapeutic purposes. ACKNOWLEDGMENTS M.G.N. was supported by an ERC Consolidator Grant (#310372) and a Spinoza grant of the Netherlands Organisation for Scientific Research. REFERENCES Arts, R.J.W., Moorlag, S., Novakovic, B., Li, Y., Wang, S.Y., Oosting, M., Kumar, V., Xavier, R.J.,

Wijmenga, C., Joosten, L.A.B., et al. (2018). BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe 23, 89–100 e105. Benn, C.S., Netea, M.G., Selin, L.K., and Aaby, P. (2013). A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 34, 431–439. Kamada, R., Yang, W., Zhang, Y., Patel, M.C., Yang, Y., Ouda, R., Dey, A., Wakabayashi, Y., Sakaguchi, K., Fujita, T., et al. (2018). Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc. Natl. Acad. Sci. USA 115, E9162–E9171. Kaufmann, E., Sanz, J., Dunn, J.L., Khan, N., Mendonca, L.E., Pacis, A., Tzelepis, F., Pernet, E., Dumaine, A., Grenier, J.C., et al. (2018). BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell 172, 176–190. Machiels, B., Dourcy, M., Xiao, X., Javaux, J., Mesnil, C., Sabatel, C., Desmecht, D., Lallemand, F., Martinive, P., Hammad, H., et al. (2017). A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18, 1310–1320. Mehta, D., Petes, C., Gee, K., and Basta, S. (2015). The Role of Virus Infection in Deregulating the Cytokine Response to Secondary Bacterial Infection. J. Interferon Cytokine Res. 35, 925–934. Mitroulis, I., Ruppova, K., Wang, B., Chen, L.S., Grzybek, M., Grinenko, T., Eugster, A., Troullinaki, M., Palladini, A., Kourtzelis, I., et al. (2018). Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell 172, 147–161. Netea, M.G., Joosten, L.A., Latz, E., Mills, K.H., Natoli, G., Stunnenberg, H.G., O’Neill, L.A., and Xavier, R.J. (2016). Trained immunity: A program of innate immune memory in health and disease. Science 352, aaf1098. Wendeln, A.C., Degenhardt, K., Kaurani, L., Gertig, M., Ulas, T., Jain, G., Wagner, J., Ha¨sler, L.M., Wild, K., Skodras, A., et al. (2018). Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332–338. Yao, Y., Jeyanathan, M., Haddadi, S., Barra, N.G., Vaseghi-Shanjani, M., Damjanovic, D., Lai, R., Afkhami, S., Chen, Y., Dvorkin-Gheva, A., et al. (2018). Macrophages Requires T Cell Help and Is Critical to Trained Immunity. Cell 175, this issue, 1634–1650.

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