[en] Gammaherpesviruses (γHVs) have coevolved with their host, leading to a remarkably high infection prevalence and establishment of latency. The lifelong persistence of γHVs in hosts appears to broadly shape host immunity, and we show here that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse γHV, drives the recruitment of Ly6Chi monocytes (MOs) into the airway, thereby modulating the host immune response. The absence of Ly6Chi MOs is associated with severe virus-induced immunopathology and the systemic release of inflammatory mediators. Mechanistically, MuHV-4-imprinted MOs recruit CD4 T cells to the airways and trigger immunosuppressive signaling pathways through the PD-L1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6Chi MOs in modulating CD4 T cell functions and reveal pathways that could be targeted therapeutically to reduce detrimental immunopathological responses associated with respiratory viral infections.
Disciplines :
Immunology & infectious disease
Author, co-author :
Maquet, Céline ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
Baiwir, Jérôme ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
Loos, Pauline ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
Rodriguez Rodriguez, Lucia ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Javaux, Justine ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Sandor, Rémy ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Perin, Fabienne ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Fallon, Padraic G ; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Mack, Matthias; Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
Cataldo, Didier ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
Gillet, Laurent ✱; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Machiels, Bénédicte ✱; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI)
✱ These authors have contributed equally to this work.
Language :
English
Title :
Ly6Chi monocytes balance regulatory and cytotoxic CD4 T cell responses to control virus-induced immunopathology.
Y. Belkaid, T. W. Hand, Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).
C. M. Lloyd, B. J. Marsland, Lung homeostasis: Influence of age, microbes, and the immune system. Immunity 46, 549–561 (2017).
J. L. Schultze, A. C. Aschenbrenner, COVID-19 and the human innate immune system. Cell 184, 1671–1692 (2021).
C. Shi, E. G. Pamer, Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762–774 (2011).
M. Merad, J. C. Martin, Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat. Rev. Immunol. 20, 355–362 (2020).
E. Cesarman, Gammaherpesviruses and lymphoproliferative disorders. Annu. Rev. Pathol. Mech. Dis. 9, 349–372 (2014).
E. S. Barton, D. W. White, J. S. Cathelyn, K. A. Brett-McClellan, M. Engle, M. S. Diamond, V. L. Miller, H. W. Virgin IV, Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).
D. W. White, R. Suzanne Beard, E. S. Barton, Immune modulation during latent herpesvirus infection. Immunol. Rev. 245, 189–208 (2012).
E. Barton, P. Mandal, S. H. Speck, Pathogenesis and host control of gammaherpesviruses: Lessons from the mouse. Annu. Rev. Immunol. 29, 351–397 (2011).
B. Machiels, M. Dourcy, X. Xiao, J. Javaux, C. Mesnil, C. Sabatel, D. Desmecht, F. Lallemand, P. Martinive, H. Hammad, M. Guilliams, B. Dewals, A. Vanderplasschen, B. N. Lambrecht, F. Bureau, L. Gillet, A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18, 1310–1320 (2017).
M. H. Askenase, S.-J. Han, A. L. Byrd, D. MoraisdaFonseca, N. Bouladoux, C. Wilhelm, J. E. Konkel, T. W. Hand, N. Lacerda-Queiroz, X.-z. Su, G. Trinchieri, J. R. Grainger, Y. Belkaid, Bone-marrow-resident NK cells prime monocytes for regulatory function during infection. Immunity 42, 1130–1142 (2015).
N. V. Serbina, E. G. Pamer, Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–318 (2006).
M. Mack, J. Cihak, C. Simonis, B. Luckow, A. E. I. Proudfoot, J. Plachý, H. Brühl, M. Frink, H.-J. Anders, V. Vielhauer, J. Pfirstinger, M. Stangassinger, D. Schlöndorff, Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J. Immunol. 166, 4697–4704 (2001).
T. Lenac Rovis, P. Kucan Brlic, N. Kaynan, V. Juranic Lisnic, I. Brizic, S. Jordan, A. Tomic, D. Kvestak, M. Babic, P. Tsukerman, M. Colonna, U. Koszinowski, M. Messerle, O. Mandelboim, A. Krmpotic, S. Jonjic, Inflammatory monocytes and NK cells play a crucial role in DNAM-1–dependent control of cytomegalovirus infection. J. Exp. Med. 213, 1835–1850 (2016).
C. D. Conrady, M. Zheng, N. A. Mandal, N. van Rooijen, D. J. J. Carr, IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice. Mucosal Immunol. 6, 45–55 (2012).
M. Rolot, A. M. Dougall, A. Chetty, J. Javaux, T. Chen, X. Xiao, B. Machiels, M. E. Selkirk, R. M. Maizels, C. Hokke, O. Denis, F. Brombacher, A. Vanderplasschen, L. Gillet, W. G. C. Horsnell, B. G. Dewals, Helminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection. Nat. Commun. 9, 4516 (2018).
H. Xiong, E. G. Pamer, Monocytes and infection: Modulator, messenger and effector. Immunobiology 220, 210–214 (2015).
J. V. Camp, C. B. Jonsson, A role for neutrophils in viral respiratory disease. Front. Immunol. 8, 550 (2017).
Q. Liu, Y. H. Zhou, Z. Q. Yang, The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell. Mol. Immunol. 13, 3–10 (2016).
Y. Tang, J. Liu, D. Zhang, Z. Xu, J. Ji, C. Wen, Cytokine storm in COVID-19: The current evidence and treatment strategies. Front. Immunol. 11, 1708 (2020).
A. L. Croxford, M. Lanzinger, F. J. Hartmann, B. Schreiner, F. Mair, P. Pelczar, B. E. Clausen, S. Jung, M. Greter, B. Becher, The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 43, 502–514 (2015).
H. Bouabe, Y. Liu, M. Moser, M. R. Bosl, J. Heesemann, Novel highly sensitive IL-10–βlactamase reporter mouse reveals cells of the innate immune system as a substantial source of IL-10 in vivo. J. Immunol. 187, 3165–3176 (2011).
C. Bosteels, K. Neyt, M. Vanheerswynghels, M. J. van Helden, D. Sichien, N. Debeuf, S. De Prijck, V. Bosteels, N. Vandamme, L. Martens, Y. Saeys, E. Louagie, M. Lesage, D. L. Williams, S. C. Tang, J. U. Mayer, F. Ronchese, C. L. Scott, H. Hammad, M. Guilliams, B. N. Lambrecht, Inflammatory type 2 cDCs acquire features of cDC1s and macrophages to orchestrate immunity to respiratory virus infection. Immunity 52, 1039–1056.e9 (2020).
C. Mesnil, C. M. Sabatel, T. Marichal, M. Toussaint, D. Cataldo, P.-V. Drion, P. Lekeux, F. Bureau, C. J. Desmet, Resident CD11b+Ly6C− lung dendritic cells are responsible for allergic airway sensitization to house dust mite in mice. PLOS ONE 7, e53242 (2012).
Y. Ohmori, T. A. Hamilton, IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages. J. Immunol. 159, 5474–5482 (1997).
R. A. Rahimi, A. D. Luster, Chemokines: Critical regulators of memory T cell development, maintenance, and function. Adv. Immunol. 138, 71–98 (2018).
R. Tokunaga, W. Zhang, M. Naseem, A. Puccini, M. D. Berger, S. Soni, M. McSkane, H. Baba, H.-J. Lenz, CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation—A target for novel cancer therapy. Cancer Treat. Rev. 63, 40–47 (2018).
M. Stoeckius, S. Zheng, B. Houck-Loomis, S. Hao, B. Z. Yeung, W. M. Mauck, P. Smibert, R. Satija, Cell hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics. Genome Biol. 19, 224 (2018).
L. Spinelli, S. Carpentier, F. Montanana Sanchis, M. Dalod, T.-P. V. Manh, BubbleGUM: Automatic extraction of phenotype molecular signatures and comprehensive visualization of multiple gene set enrichment analyses. BMC Genomics 16, 814 (2015).
P. A. Szabo, H. M. Levitin, M. Miron, M. E. Snyder, T. Senda, J. Yuan, Y. L. Cheng, E. C. Bush, P. Dogra, P. Thapa, D. L. Farber, P. A. Sims, Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat. Commun. 10, 4706 (2019).
L. Gabryšová, M. Alvarez-Martinez, R. Luisier, L. S. Cox, J. Sodenkamp, C. Hosking, D. Pérez-Mazliah, C. Whicher, Y. Kannan, K. Potempa, X. Wu, L. Bhaw, H. Wende, M. H. Sieweke, G. Elgar, M. Wilson, J. Briscoe, V. Metzis, J. Langhorne, N. M. Luscombe, A. O’Garra, c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells. Nat. Immunol. 19, 497–507 (2018).
C. D. Slade, K. L. Reagin, H. G. Lakshmanan, K. D. Klonowski, W. T. Watford, Placenta-specific 8 limits IFNγ production by CD4 T cells in vitro and promotes establishment of influenza-specific CD8 T cells in vivo. PLOS ONE 15, e0235706 (2020).
A. E. Lukacher, L. A. Morrison, V. L. Braciale, B. Malissen, T. J. Braciale, Expression of specific cytolytic activity by H-2I region-restricted, influenza virus-specific T lymphocyte clones. J. Exp. Med. 162, 171–187 (1985).
J. J. Zaunders, W. B. Dyer, B. Wang, M. L. Munier, M. Miranda-Saksena, R. Newton, J. Moore, C. R. Mackay, D. A. Cooper, N. K. Saksena, A. D. Kelleher, Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection. Blood 103, 2238–2247 (2004).
K. A. Stuller, E. Flaño, CD4 T cells mediate killing during persistent gammaherpesvirus 68 infection. J. Virol. 83, 4700–4703 (2009).
R. Browaeys, W. Saelens, Y. Saeys, NicheNet: Modeling intercellular communication by linking ligands to target genes. Nat. Methods 17, 159–162 (2020).
P. J. Norris, H. F. Moffett, O. O. Yang, D. E. Kaufmann, M. J. Clark, M. M. Addo, E. S. Rosenberg, Beyond help: Direct effector functions of human immunodeficiency virus type 1-specific CD4+ T cells. J. Virol. 78, 8844–8851 (2004).
D. M. Brown, A. T. Lampe, A. M. Workman, The differentiation and protective function of cytolytic CD4 T cells in influenza infection. Front. Immunol. 7, 93 (2016).
D. Y. Oh, S. S. Kwek, S. S. Raju, T. Li, E. McCarthy, E. Chow, D. Aran, A. Ilano, C. C. S. Pai, C. Rancan, K. Allaire, A. Burra, Y. Sun, M. H. Spitzer, S. Mangul, S. Porten, M. V. Meng, T. W. Friedlander, C. J. Ye, L. Fong, Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181, 1612–1625.e13 (2018).
A. Cachot, M. Bilous, Y.-C. Liu, X. Li, M. Saillard, M. Cenerenti, G. A. Rockinger, T. Wyss, P. Guillaume, J. Schmidt, R. Genolet, G. Ercolano, M. P. Protti, W. Reith, K. Ioannidou, L. de Leval, J. A. Trapani, G. Coukos, A. Harari, D. E. Speiser, A. Mathis, D. Gfeller, H. Altug, P. Romero, C. Jandus, Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer. Sci. Adv. 7, eabe3348 (2021).
S. Verma, D. Weiskopf, A. Gupta, B. McDonald, B. Peters, A. Sette, C. A. Benedict, Cytomegalovirus-specific CD4 T cells are cytolytic and mediate vaccine protection. J. Virol. 90, 650–658 (2016).
T. Maehara, N. Kaneko, C. A. Perugino, H. Mattoo, J. Kers, H. Allard-Chamard, V. S. Mahajan, H. Liu, S. J. H. Murphy, M. Ghebremichael, D. Fox, A. S. Payne, R. Lafyatis, J. H. Stone, D. Khanna, S. Pillai, Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis. J. Clin. Invest. 130, 2451–2464 (2020).
J. A. Juno, D. van Bockel, S. J. Kent, A. D. Kelleher, J. J. Zaunders, C. M. L. Munier, Cytotoxic CD4 T cells—Friend or foe during viral infection? Front. Immunol. 8, 19 (2017).
E. R. Jellison, S.-K. Kim, R. M. Welsh, Cutting edge: MHC class II-restricted killing in vivo during viral infection. J. Immunol. 174, 614–618 (2005).
N. A. Scott, Y. Zhao, B. Krishnamurthy, S. I. Mannering, T. W. H. Kay, H. E. Thomas, IFNγ-induced MHC class II expression on islet endothelial cells is an early marker of insulitis but is not required for diabetogenic CD4+ T cell migration. Front. Immunol. 9, 2800 (2018).
J. E. Wosen, D. Mukhopadhyay, C. Macaubas, E. D. Mellins, Epithelial MHC class II expression and its role in antigen presentation in the gastrointestinal and respiratory tracts. Front. Immunol. 9, 2144 (2018).
P. Smith, L. A. Jeffers, M. Koval, Measurement of lung vessel and epithelial permeability in vivo with evans blue. Methods Mol. Biol. 2367, 137–148 (2021).
M. E. Keir, M. J. Butte, G. J. Freeman, A. H. Sharpe, PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).
G. Schönrich, M. J. Raftery, The PD-1/PD-L1 axis and virus infections: A delicate balance. Front. Cell. Infect. Microbiol. 9, 207 (2019).
H. W. Virgin, The virome in mammalian physiology and disease. Cell 157, 142–150 (2014).
P. Brodin, V. Jojic, T. Gao, S. Bhattacharya, C. J. Angel, D. Furman, S. Shen-Orr, C. L. Dekker, G. E. Swan, A. J. Butte, H. T. Maecker, M. M. Davis, Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).
P. C. Doherty, J. P. Christensen, G. T. Belz, P. G. Stevenson, M. Y. Sangster, Dissecting the host response to a γ-herpesvirus. Philos. Trans. R. Soc. B Biol. Sci. 356, 581–593 (2001).
P. G. Stevenson, Immune evasion by gamma-herpesviruses. Curr. Opin. Immunol. 16, 456–462 (2004).
F. Saito, T. Ito, J. M. Connett, M. A. Schaller, W. F. Carson, C. M. Hogaboam, R. Rochford, S. L. Kunkel, MHV68 latency modulates the host immune response to influenza A virus. Inflammation 36, 1295–1303 (2013).
A. Haque, N. Rachinel, M. R. Quddus, S. Haque, L. H. Kasper, E. Usherwood, Co-infection of malaria and γ-herpesvirus: Exacerbated lung inflammation or cross-protection depends on the stage of viral infection. Clin. Exp. Immunol. 138, 396–404 (2004).
M. Dourcy, C. Maquet, L. Dams, G. Gilliaux, J. Javaux, D. Desmecht, M. Mack, B. G. Dewals, B. Machiels, L. Gillet, A gammaherpesvirus licenses CD8 T cells to protect the host from pneumovirus-induced immunopathologies. Mucosal Immunol. 13, 799–813 (2020).
Y. Yao, M. Jeyanathan, S. Haddadi, N. G. Barra, M. Vaseghi-Shanjani, D. Damjanovic, R. Lai, S. Afkhami, Y. Chen, A. Dvorkin-Gheva, C. S. Robbins, J. D. Schertzer, Z. Xing, Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175, 1634–1650.e17 (2018).
D. Weiskopf, D. J. Bangs, J. Sidney, R. V. Kolla, A. D. de Silva, A. M. de Silva, S. Crotty, B. Peters, A. Sette, Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity. Proc. Natl. Acad. Sci. U.S.A. 112, E4256–E4263 (2015).
B. J. Meckiff, K. Ladell, J. E. McLaren, G. B. Ryan, A. M. Leese, E. A. James, D. A. Price, H. M. Long, Primary EBV infection induces an acute wave of activated antigen-specific cytotoxic CD4+ T cells. J. Immunol. 203, 1276–1287 (2019).
L. M. Peeters, M. Vanheusden, V. Somers, B. van Wijmeersch, P. Stinissen, B. Broux, N. Hellings, Cytotoxic CD4+ T cells drive multiple sclerosis progression. Front. Immunol. 8, 1160 (2017).
B. J. Meckiff, C. Ramírez-Suástegui, V. Fajardo, S. J. Chee, A. Kusnadi, H. Simon, S. Eschweiler, A. Grifoni, E. Pelosi, D. Weiskopf, A. Sette, F. Ay, G. Seumois, C. H. Ottensmeier, P. Vijayanand, Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19. Cell 183, 1340–1353.e16 (2020).
K. Hashimoto, T. Kouno, T. Ikawa, N. Hayatsu, Y. Miyajima, H. Yabukami, T. Terooatea, T. Sasaki, T. Suzuki, M. Valentine, G. Pascarella, Y. Okazaki, H. Suzuki, J. W. Shin, A. Minoda, I. Taniuchi, H. Okano, Y. Arai, N. Hirose, P. Carninci, Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians. Proc. Natl. Acad. Sci. U.S.A. 116, 24242–24251 (2019).
W. Ouyang, S. Rutz, N. K. Crellin, P. A. Valdez, S. G. Hymowitz, Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).
A. M. Siegel, J. H. Herskowitz, S. H. Speck, The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. PLOS Pathog. 4, e1000039 (2008).
K. W. Moore, P. Vieira, D. F. Fiorentino, M. L. Trounstine, T. A. Khan, T. R. Mosmann, Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science 248, 1230–1234 (1990).
A. K. Kimball, L. M. Oko, R. E. Kaspar, L. F. van Dyk, E. T. Clambey, High-dimensional characterization of IL-10 production and IL-10–dependent regulation during primary gammaherpesvirus infection. ImmunoHorizons 3, 94–109 (2019).
J. Sun, A. Cardani, A. K. Sharma, V. E. Laubach, R. S. Jack, W. Müller, T. J. Braciale, Autocrine regulation of pulmonary inflammation by effector T-cell derived IL-10 during infection with respiratory syncytial virus. PLOS Pathog. 7, e1002173 (2011).
J. Attanasio, E. J. Wherry, Costimulatory and coinhibitory receptor pathways in infectious disease. Immunity 44, 1052–1068 (2016).
M. J. Butte, M. E. Keir, T. B. Phamduy, A. H. Sharpe, G. J. Freeman, Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007).
L. Wang, K. Pino-Lagos, V. C. De Vries, I. Guleria, M. H. Sayegh, R. J. Noelle, Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc. Natl. Acad. Sci. U.S.A. 105, 9331–9336 (2008).
D. B. Johnson, J. M. Balko, M. L. Compton, S. Chalkias, J. Gorham, Y. Xu, M. Hicks, I. Puzanov, M. R. Alexander, T. L. Bloomer, J. R. Becker, D. A. Slosky, E. J. Phillips, M. A. Pilkinton, L. Craig-Owens, N. Kola, G. Plautz, D. S. Reshef, J. S. Deutsch, R. P. Deering, B. A. Olenchock, A. H. Lichtman, D. M. Roden, C. E. Seidman, I. J. Koralnik, J. G. Seidman, R. D. Hoffman, J. M. Taube, L. A. Diaz, R. A. Anders, J. A. Sosman, J. J. Moslehi, Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749–1755 (2016).
R. A. Marsh, Epstein-Barr virus and hemophagocytic lymphohistiocytosis. Front. Immunol. 8, 1902 (2018).
S. Grebinoski, A. M. Gocher-Demske, D. A. A. Vignali, Catch and release: Freeing up PD-L1 ameliorates autoimmunity. Nat. Immunol. 23, 344–346 (2022).
D. Blaskovic, M. Stanceková, J. Svobodová, J. Mistríková, Isolation of five strains of herpesviruses from two species of free living small rodents. Acta Virol. 24, 468 (1980).
R. Milho, C. M. Smith, S. Marques, M. Alenquer, J. S. May, L. Gillet, M. Gaspar, S. Efstathiou, J. P. Simas, P. G. Stevenson, In vivo imaging of murid herpesvirus-4 infection. J. Gen. Virol. 90, 21–32 (2009).
Z. Gu, L. Gu, R. Eils, M. Schlesner, B. Brors, Circlize implements and enhances circular visualization in R. Bioinformatics 30, 2811–2812 (2014).
