Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo
Marc Dalod, Thais P Salazar-Mather, Lene Malmgaard, Casey Lewis, Carine Asselin-Paturel, Francine Brière, Giorgio Trinchieri, Christine A Biron, Marc Dalod, Thais P Salazar-Mather, Lene Malmgaard, Casey Lewis, Carine Asselin-Paturel, Francine Brière, Giorgio Trinchieri, Christine A Biron
Abstract
Interferon (IFN)-alpha/beta and interleukin (IL)-12 are cytokines critical in defense against viruses, but their cellular sources and mechanisms of regulation for in vivo expression remain poorly characterized. The studies presented here identified a novel subset of dendritic cells (DCs) as major producers of the cytokines during murine cytomegalovirus (MCMV) but not lymphocytic choriomeningitis virus (LCMV) infections. These DCs differed from those activated by Toxoplasma antigen but were related to plasmacytoid cells, as assessed by their CD8alpha(+)Ly6G/C(+)CD11b(-) phenotype. Another DC subset (CD8alpha(2)Ly6G/C(-)CD11b(+)) also contributed to IL-12 production in MCMV-infected immunocompetent mice, modestly. However, it dramatically increased IL-12 expression in the absence of IFN-alpha/beta functions. Conversely, IFN-alpha/beta production was greatly reduced under these conditions. Thus, a cross-regulation of DC subset cytokine responses was defined, whereby secretion of type I IFNs by CD8alpha(+) DCs resulted in responses limiting IL-12 expression by CD11b(+) DCs but enhancing overall IFN-alpha/beta production. Taken together, these data indicate that CD8alpha(+)Ly6G/C(+)CD11b(-) DCs play important roles in limiting viral replication and regulating immune responses, through cytokine production, in some but not all viral infections. They also illustrate the plasticity of cellular sources for innate cytokines in vivo and provide new insights into the roles of IFNs in shaping immune responses to viruses.
Figures
References
- Biron, C.A. 1999. Initial and innate responses to viral infections: pattern setting in immunity or disease. Curr. Opin. Microbiol. 2:374–381.
- Hochrein, H., M. O'Keeffe, T. Luft, S. Vandenabeele, R.J. Grumont, E. Maraskovsky, and K. Shortman. 2000. IL-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J. Exp. Med. 192:823–833.
- Marie, I., J.E. Durbin, and D.E. Levy. 1998. Differential viral induction of distinct interferon-α genes by positive feedback through interferon regulatory factor-7. EMBO J. 17:6660–6669.
- Nguyen, K.B., L.P. Cousens, L.A. Doughty, G.C. Pien, J.E. Durbin, and C.A. Biron. 2000. Interferon-α/β-mediated inhibition and promotion of interferon-γ: STAT1 resolves a paradox. Nat. Immunol. 1:70–76.
- Cousens, L.P., J.S. Orange, H.C. Su, and C.A. Biron. 1997. Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro and endogenously during viral infection. Proc. Natl. Acad. Sci. USA. 94:634–639.
- McRae, B.L., R.T. Semnani, M.P. Hayes, and G.A. van Seventer. 1998. Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development. J. Immunol. 160:4298–4304.
- Karp, C.L., C.A. Biron, and D.N. Irani. 2000. Interferon-β in multiple sclerosis: is IL-12 suppression the key? Immunol. Today. 21:24–28.
- Byrnes, A.A., X. Ma, P. Cuomo, K. Park, L. Wahl, S.F. Wolf, H. Zhou, G. Trinchieri, and C.L. Karp. 2001. Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity. Eur. J. Immunol. 31:2026–2034.
- Grabbe, S., E. Kampgen, and G. Schuler. 2000. Dendritic cells: multi-lineal and multi-functional. Immunol. Today. 21:431–433.
- Liu, Y.J., H. Kanzler, V. Soumelis, and M. Gilliet. 2001. Dendritic cell lineage, plasticity and cross-regulation. Nat. Immunol. 2:585–589.
- Maldonado-Lopez, R., T. De Smedt, P. Michel, J. Godfroid, B. Pajak, C. Heirman, K. Thielemans, O. Leo, J. Urbain, and M. Moser. 1999. CD8α1 and CD8α2 subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189:587–592.
- Hochrein, H., K. Shortman, D. Vremec, B. Scott, P. Hertzog, and M. O'Keeffe. 2001. Differential production of IL-12, IFN-α, and IFN-γ by mouse dendritic cell subsets. J. Immunol. 166:5448–5455.
- Asselin-Paturel, C., A. Boonstra, M. Dalod, I. Durand, N. Yessaad, C. Dezutter-Dambuyant, A. Vicari, A. O'Garra, C. Biron, and G. Trinchieri. 2001. Mouse type I interferon producing cells are immature antigen-presenting cells with plasmacytoid morphology. Nat. Immunol. 2:1144–1150.
- Moser, M., and K.M. Murphy. 2000. Dendritic cell regulation of TH1-TH2 development. Nat. Immunol. 1:199–205.
- Reis e Sousa, C., S. Hieny, T. Scharton-Kersten, D. Jankovic, H. Charest, R.N. Germain, and A. Sher. 1997. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med. 186:1819–1829.
- Sam, H., and M.M. Stevenson. 1999. Early IL-12 p70, but not p40, production by splenic macrophages correlates with host resistance to blood-stage Plasmodium chabaudi AS malaria. Clin. Exp. Immunol. 117:343–349.
- Aliberti, J.C., M.A. Cardoso, G.A. Martins, R.T. Gazzinelli, L.Q. Vieira, and J.S. Silva. 1996. Interleukin-12 mediates resistance to Trypanosoma cruzi in mice and is produced by murine macrophages in response to live trypomastigotes. Infect. Immun. 64:1961–1967.
- Malmgaard, L., S.R. Paludan, S.C. Mogensen, and S. Ellermann-Eriksen. 2000. Herpes simplex virus type 2 induces secretion of IL-12 by macrophages through a mechanism involving NF-κB. J. Gen. Virol. 12:3011–3020.
- Bliss, S.K., Y. Zhang, and E.Y. Denkers. 1999. Murine neutrophil stimulation by Toxoplasma gondii antigen drives high level production of IFN-γ-independent IL-12. J. Immunol. 163:2081–2088.
- Tateda, K., T.A. Moore, J.C. Deng, M.W. Newstead, X. Zeng, A. Matsukawa, M.S. Swanson, K. Yamaguchi, and T.J. Standiford. 2001. Early recruitment of neutrophils determines subsequent T1/T2 host responses in a murine model of Legionella pneumophila pneumonia. J. Immunol. 166:3355–3361.
- Petrofsky, M., and L.E. Bermudez. 1999. Neutrophils from Mycobacterium avium-infected mice produce TNF-α, IL-12, and IL-1β and have a putative role in early host response. Clin. Immunol. 91:354–358.
- Orange, J.S., and C.A. Biron. 1996. An absolute and restricted requirement for IL-12 in natural killer cell IFN-γ production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J. Immunol. 156:1138–1142.
- Orange, J.S., and C.A. Biron. 1996. Characterization of early IL-12, IFN-α/β, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J. Immunol. 156:4746–4756.
- Ruzek, M.C., A.H. Miller, S.M. Opal, B.D. Pearce, and C.A. Biron. 1997. Characterization of early cytokine responses and an IL-6–dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection. J. Exp. Med. 185:1185–1192.
- Biron, C.A., K.B. Nguyen, G.C. Pien, L.P. Cousens, and T.P. Salazar-Mather. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17:189–220.
- Pien, G.C., A.R. Satoskar, K. Takeda, S. Akira, and C.A. Biron. 2000. Cutting edge: selective IL-18 requirements for induction of compartmental IFN-γ responses during viral infection. J. Immunol. 165:4787–4791.
- Wang, B., C. Biron, J. She, K. Higgins, M.J. Sunshine, E. Lacy, N. Lonberg, and C. Terhorst. 1994. A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3ɛ gene. Proc. Natl. Acad. Sci. USA. 91:9402–9406.
- Orange, J.S., B. Wang, C. Terhorst, and C.A. Biron. 1995. Requirement for natural killer cell-produced interferon-γ in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J. Exp. Med. 182:1045–1056.
- Schulz, O., D.A. Edwards, M. Schito, J. Aliberti, S. Manickasingham, A. Sher, and C. Reis e Sousa. 2000. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity. 13:453–462.
- Nguyen, K.B., and C.A. Biron. 1999. Synergism for cytokine-mediated disease during concurrent endotoxin and viral challenges: roles for NK and T cell IFN-γ production. J. Immunol. 162:5238–5246.
- Deonarain, R., A. Alcami, M. Alexiou, M.J. Dallman, D.R. Gewert, and A.C. Porter. 2000. Impaired antiviral response and α/β interferon induction in mice lacking β interferon. J. Virol. 74:3404–3409.
- Salazar-Mather, T.P., T.A. Hamilton, and C.A. Biron. 2000. A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense. J. Clin. Invest. 105:985–993.
- Eloranta, M.L., and G.V. Alm. 1999. Splenic marginal metallophilic macrophages and marginal zone macrophages are the major interferon-α/β producers in mice upon intravenous challenge with herpes simplex virus. Scand. J. Immunol. 49:391–394.
- Sevilla, N., S. Kunz, A. Holz, H. Lewicki, D. Homann, H. Yamada, K.P. Campbell, J.C. de La Torre, and M.B. Oldstone. 2000. Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells. J. Exp. Med. 192:1249–1260.
- Huang, L.Y., C. Reis e Sousa, Y. Itoh, J. Inman, and D.E. Scott. 2001. IL-12 induction by a TH1-inducing adjuvant in vivo: dendritic cell subsets and regulation by IL-10. J. Immunol. 167:1423–1430.
- Biron, C.A., M. Dalod, and T.P. Salazar-Mather. 2001. Innate immunity and viral infections. Immunity to Infections. S.H.E. Kaufmann, A. Sher, and R. Ahmed, editors. American Society for Microbiology. 139–160.
- Biron, C.A. 2001. Interferons α and β as immune regulators: a new look. Immunity. 14:661–664.
- den Haan, J.M., S.M. Lehar, and M.J. Bevan. 2000. CD8+ but not CD8− dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192:1685–1696.
- Pooley, J.L., W.R. Heath, and K. Shortman. 2001. Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8− dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells. J. Immunol. 166:5327–5330.
- Kronin, V., C.J. Fitzmaurice, I. Caminschi, K. Shortman, D.C. Jackson, and L.E. Brown. 2001. Differential effect of CD8+ and CD8− dendritic cells in the stimulation of secondary CD4+ T cells. Int. Immunol. 13:465–473.
Source: PubMed