1932
0

Annual Review of Immunology

Volume 43, 2025

From Cytokines to Tuberculosis and Back: My Journey to Understanding the Immune Response to Infection

  • Anne O'Garra1
  • Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London, United Kingdom; email: [email protected]
  • Vol. 43:1-28 (Volume publication date April 2025)
  • Copyright © 2025 by The Francis Crick Institute.
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

I felt honored by the invitation to write this autobiography, although it was an arduous task to describe my journey through science: first bacterial adhesion, then cytokine function, and then immune responses in tuberculosis. Since only seven women had been authors of autobiographies for the , I felt I couldn't refuse to contribute to Volume 43 of the journal. Moreover, this was a good occasion to record my appreciation to all the lab members and collaborators for their contributions over the last 40 years, to remember the exciting times, and to reflect on the obstacles we faced. I often reflect on this line that is commonly attributed to Winston Churchill: Success is not final; failure is not fatal: It is the courage to continue that counts. What kept me going was a burning desire to know how things work and find enjoyment in the discovery. This passion to understand immune responses to infection remains with me to this day. I thank all those I have interacted with for the support and friendship they provided.

Keyword(s): autobiography, cytokine, dendritic cells, IL-10, IL-12, macrophages, T helper cells, Th1, Th2, tuberculosis, type I interferon
Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-010824-041601
2025-04-25
2025-06-19
Loading full text...

Full text loading...

/deliver/fulltext/immunol/43/1/annurev-immunol-010824-041601.html?itemId=/content/journals/10.1146/annurev-immunol-010824-041601&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Gibbons RJ, van Houte J. 1971.. Selective bacterial adherence to oral epithelial surfaces and its role as an ecological determinant. . Infect. Immun. 3::567–73
     [Crossref] [Google Scholar]
  2. 2.
    O'Garra A, Ward JB. 1983.. Adhesion of coagulase negative Staphylococci to human epithelial cells. Paper presented at the 83rd Annual Meeting of the American Society for Microbiology, New Orleans:, March 6–11
    [Google Scholar]
  3. 3.
    O'Garra A, Umland S, De France T, Christiansen J. 1988.. ‘ B-cell factors’ are pleiotropic. . Immunol. Today 9::45–54
     [Crossref] [Google Scholar]
  4. 4.
    Gillis S, Smith KA. 1977.. Long term culture of tumour-specific cytotoxic T cells. . Nature 268::154–56
     [Crossref] [Google Scholar]
  5. 5.
    Smith KA, Ruscetti FW. 1981.. T-cell growth factor and the culture of cloned functional T cells. . Adv. Immunol. 31::137–75
     [Crossref] [Google Scholar]
  6. 6.
    Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, et al. 1983.. Structure and expression of a cloned cDNA for human interleukin-2. . Nature 302::305–10
     [Crossref] [Google Scholar]
  7. 7.
    Yokota T, Arai N, Lee F, Rennick D, Mosmann T, Arai K. 1985.. Use of a cDNA expression vector for isolation of mouse interleukin 2 cDNA clones: expression of T-cell growth-factor activity after transfection of monkey cells. . PNAS 82::68–72
     [Crossref] [Google Scholar]
  8. 8.
    Howard M, Farrar J, Hilfiker M, Johnson B, Takatsu K, et al. 1982.. Identification of a T cell-derived B cell growth factor distinct from interleukin 2. . J. Exp. Med. 155::914–23
     [Crossref] [Google Scholar]
  9. 9.
    Howard M, Paul WE. 1983.. Regulation of B-cell growth and differentiation by soluble factors. . Annu. Rev. Immunol. 1::307–33
     [Crossref] [Google Scholar]
  10. 10.
    Dutton RW, Wetzel GD, Swain SL. 1984.. Partial purification and characterization of a BCGFII from EL4 culture supernatants. . J. Immunol. 132::2451–56
     [Crossref] [Google Scholar]
  11. 11.
    Hübner L, Schimpl A, Wecker E. 1980.. Partial characterization and purification of murine T helper cell replacing factor (TRF)–III: further purification steps and serological characteristics. . Mol. Immunol. 17::591–99
     [Crossref] [Google Scholar]
  12. 12.
    Harada N, Kikuchi Y, Tominaga A, Takaki S, Takatsu K. 1985.. BCGFII activity on activated B cells of a purified murine T cell–replacing factor (TRF) from a T cell hybridoma (B151K12). . J. Immunol. 134::3944–51
     [Crossref] [Google Scholar]
  13. 13.
    Takatsu K, Harada N, Hara Y, Takahama Y, Yamada G, et al. 1985.. Purification and physicochemical characterization of murine T cell replacing factor (TRF). . J. Immunol. 134::382–89
     [Crossref] [Google Scholar]
  14. 14.
    Isakson PC, Pure E, Vitetta ES, Krammer PH. 1982.. T cell-derived B cell differentiation factor(s). Effect on the isotype switch of murine B cells. . J. Exp. Med. 155::734–48
     [Crossref] [Google Scholar]
  15. 15.
    Bergstedt-Lindqvist S, Sideras P, MacDonald HR, Severinson E. 1984.. Regulation of Ig class secretion by soluble products of certain T-cell lines. . Immunol. Rev. 78::25–50
     [Crossref] [Google Scholar]
  16. 16.
    Okada M, Sakaguchi N, Yoshimura N, Hara H, Shimizu K, et al. 1983.. B cell growth factors and B cell differentiation factor from human T hybridomas. Two distinct kinds of B cell growth factor and their synergism in B cell proliferation. . J. Exp. Med. 157::583–90
     [Crossref] [Google Scholar]
  17. 17.
    Teranishi T, Hirano T, Arima N, Onoue K. 1982.. Human helper T cell factor(s) (ThF). II. Induction of IgG production in B lymphoblastoid cell lines and identification of T cell-replacing factor- (TRF) like factor(s). . J. Immunol. 128::1903–8
     [Crossref] [Google Scholar]
  18. 18.
    Hedrick SM, Cohen DI, Nielsen EA, Davis MM. 1984.. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. . Nature 308::149–53
     [Crossref] [Google Scholar]
  19. 19.
    Yanagi Y, Yoshikai Y, Leggett K, Clark SP, Aleksander I, Mak TW. 1984.. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. . Nature 308::145–49
     [Crossref] [Google Scholar]
  20. 20.
    Sanderson CJ, Warren DJ, Strath M. 1985.. Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3, and functional properties of eosinophils produced in cultures. . J. Exp. Med. 162::60–74
     [Crossref] [Google Scholar]
  21. 21.
    Strath M, Warren DJ, Sanderson CJ. 1985.. Detection of eosinophils using an eosinophil peroxidase assay. Its use as an assay for eosinophil differentiation factors. . J. Immunol. Methods 83::209–15
     [Crossref] [Google Scholar]
  22. 22.
    Warren DJ, Sanderson CJ. 1985.. Production of a T-cell hybrid producing a lymphokine stimulating eosinophil differentiation. . Immunology 54::615–23
     [Google Scholar]
  23. 23.
    Sanderson CJ, O'Garra A, Warren DJ, Klaus GG. 1986.. Eosinophil differentiation factor also has B-cell growth factor activity: proposed name interleukin 4. . PNAS 83::437–40
     [Crossref] [Google Scholar]
  24. 24.
    Dinarello CA. 1984.. Interleukin-1. . Rev. Infect. Dis. 6::51–95
     [Crossref] [Google Scholar]
  25. 25.
    Ihle JN, Rebar L, Keller J, Lee JC, Hapel AJ. 1982.. Interleukin 3: possible roles in the regulation of lymphocyte differentiation and growth. . Immunol. Rev. 63::5–32
     [Crossref] [Google Scholar]
  26. 26.
    Smith KA. 1984.. Interleukin 2. . Annu. Rev. Immunol. 2::319–33
     [Crossref] [Google Scholar]
  27. 27.
    Noma Y, Sideras P, Naito T, Bergstedt-Lindquist S, Azuma C, et al. 1986.. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. . Nature 319::640–46
     [Crossref] [Google Scholar]
  28. 28.
    O'Garra A, Warren DJ, Holman M, Popham AM, Sanderson CJ, Klaus GG. 1986.. Interleukin 4 (B-cell growth factor II/eosinophil differentiation factor) is a mitogen and differentiation factor for preactivated murine B lymphocytes. . PNAS 83::5228–32
     [Crossref] [Google Scholar]
  29. 29.
    Kinashi T, Harada N, Severinson E, Tanabe T, Sideras P, et al. 1986.. Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II. . Nature 324::70–73
     [Crossref] [Google Scholar]
  30. 30.
    Yokota T, Coffman RL, Hagiwara H, Rennick DM, Takebe Y, et al. 1987.. Isolation and characterization of lymphokine cDNA clones encoding mouse and human IgA-enhancing factor and eosinophil colony-stimulating factor activities: relationship to interleukin 5. . PNAS 84::7388–92
     [Crossref] [Google Scholar]
  31. 31.
    Schumacher JH, O'Garra A, Shrader B, van Kimmenade A, Bond MW, et al. 1988.. The characterization of four monoclonal antibodies specific for mouse IL-5 and development of mouse and human IL-5 enzyme-linked immunosorbent. . J. Immunol. 141::1576–81
     [Crossref] [Google Scholar]
  32. 32.
    O'Garra A, Rigley KP, Holman M, McLaughlin JB, Klaus GG. 1987.. B-cell-stimulatory factor 1 reverses Fc receptor-mediated inhibition of B-lymphocyte activation. . PNAS 84::6254–58
     [Crossref] [Google Scholar]
  33. 33.
    O'Garra A, Warren DJ, Holman M, Popham AM, Sanderson CJ, Klaus GG. 1986.. Effects of cyclosporine on responses of murine B cells to T cell-derived lymphokines. . J. Immunol. 137::2220–24
     [Crossref] [Google Scholar]
  34. 34.
    Scott DW, Chace JH, Warner GL, O'Garra A, Klaus GG, Quill H. 1987.. Role of T cell-derived lymphokines in two models of B-cell tolerance. . Immunol. Rev. 99::153–71
     [Crossref] [Google Scholar]
  35. 35.
    Scott DW, O'Garra A, Warren D, Klaus GG. 1987.. Lymphoma models for B cell activation and tolerance. VI. Reversal of anti-Ig-mediated negative signaling by T cell-derived lymphokines. . J. Immunol. 139::3924–29
     [Crossref] [Google Scholar]
  36. 36.
    Yokota T, Lee F, Rennick D, Hall C, Arai N, et al. 1984.. Isolation and characterization of a mouse cDNA clone that expresses mast-cell growth-factor activity in monkey cells. . PNAS 81::1070–74
     [Crossref] [Google Scholar]
  37. 37.
    Lee F, Yokota T, Otsuka T, Gemmell L, Larson N, et al. 1985.. Isolation of cDNA for a human granulocyte-macrophage colony-stimulating factor by functional expression in mammalian cells. . PNAS 82::4360–64
     [Crossref] [Google Scholar]
  38. 38.
    Okayama H, Berg P. 1983.. A cDNA cloning vector that permits expression of cDNA inserts in mammalian cells. . Mol. Cell. Biol. 3::280–89
     [Google Scholar]
  39. 39.
    Takebe Y, Seiki M, Fujisawa J, Hoy P, Yokota K, et al. 1988.. SRα promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. . Mol. Cell. Biol. 8::466–72
     [Google Scholar]
  40. 40.
    Yokota T, Otsuka T, Mosmann T, Banchereau J, DeFrance T, et al. 1986.. Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities. . PNAS 83::5894–98
     [Crossref] [Google Scholar]
  41. 41.
    Lee F, Yokota T, Otsuka T, Meyerson P, Villaret D, et al. 1986.. Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor 1 activities and T-cell- and mast-cell-stimulating activities. . PNAS 83::2061–65
     [Crossref] [Google Scholar]
  42. 42.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. 1986.. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. . J. Immunol. 136::2348–57
     [Crossref] [Google Scholar]
  43. 43.
    Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR. 1987.. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. . J. Exp. Med. 166::1229–44
     [Crossref] [Google Scholar]
  44. 44.
    Coffman RL, Carty J. 1986.. A T cell activity that enhances polyclonal IgE production and its inhibition by interferon-gamma. . J. Immunol. 136::949–54
     [Crossref] [Google Scholar]
  45. 45.
    Coffman RL, Ohara J, Bond MW, Carty J, Zlotnik A, Paul WE. 1986.. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. . J. Immunol. 136::4538–41
     [Crossref] [Google Scholar]
  46. 46.
    Coffman RL, Shrader B, Carty J, Mosmann TR, Bond MW. 1987.. A mouse T cell product that preferentially enhances IgA production. I. Biologic characterization. . J. Immunol. 139::3685–90
     [Crossref] [Google Scholar]
  47. 47.
    Mosmann TR, Coffman RL. 1989.. Heterogeneity of cytokine secretion patterns and functions of helper T cells. . Adv. Immunol. 46::111–47
     [Crossref] [Google Scholar]
  48. 48.
    Mosmann TR, Coffman RL. 1989.. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. . Annu. Rev. Immunol. 7::145–73
     [Crossref] [Google Scholar]
  49. 49.
    Sanderson CJ, Strath M, Warren DJ, O'Garra A, Kirkwood TB. 1985.. The production of lymphokines by primary alloreactive T-cell clones: a co-ordinate analysis of 233 clones in seven lymphokine assays. . Immunology 56::575–84
     [Google Scholar]
  50. 50.
    Hsu DH, de Waal Malefyt R, Fiorentino DF, Dang MN, Vieira P, et al. 1990.. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. . Science 250::830–32
     [Crossref] [Google Scholar]
  51. 51.
    Moore KW, Vieira P, Fiorentino DF, Trounstine ML, Khan TA, Mosmann TR. 1990.. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. . Science 248::1230–34
     [Crossref] [Google Scholar]
  52. 52.
    Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE, Kastelein R, et al. 1991.. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. . PNAS 88::1172–76
     [Crossref] [Google Scholar]
  53. 53.
    Fiorentino DF, Bond MW, Mosmann TR. 1989.. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. . J. Exp. Med. 170::2081–95
     [Crossref] [Google Scholar]
  54. 54.
    O'Garra A, Chang R, Go N, Hastings R, Haughton G, Howard M. 1992.. Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. . Eur. J. Immunol. 22::711–17
     [Crossref] [Google Scholar]
  55. 55.
    O'Garra A, Stapleton G, Dhar V, Pearce M, Schumacher J, et al. 1990.. Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. . Int. Immunol. 2::821–32
     [Crossref] [Google Scholar]
  56. 56.
    Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. 1993.. Interleukin-10. . Annu. Rev. Immunol. 11::165–90
     [Crossref] [Google Scholar]
  57. 57.
    Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, et al. 1991.. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. . J. Immunol. 146::3444–51
     [Crossref] [Google Scholar]
  58. 58.
    Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. 1991.. IL-10 inhibits cytokine production by activated macrophages. . J. Immunol. 147::3815–22
     [Crossref] [Google Scholar]
  59. 59.
    Macatonia SE, Doherty TM, Knight SC, O'Garra A. 1993.. Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN-gamma production. . J. Immunol. 150::3755–65
     [Crossref] [Google Scholar]
  60. 60.
    Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. 2001.. Interleukin-10 and the interleukin-10 receptor. . Annu. Rev. Immunol. 19::683–765
     [Crossref] [Google Scholar]
  61. 61.
    de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. 1991.. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. . J. Exp. Med. 174::1209–20
     [Crossref] [Google Scholar]
  62. 62.
    de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, et al. 1991.. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. . J. Exp. Med. 174::915–24
     [Crossref] [Google Scholar]
  63. 63.
    Kornberg A. 1995.. The Golden Helix: Inside Biotech Ventures. Sausalito, Calif:.: Univ. Sci. Books
     [Google Scholar]
  64. 64.
    Swain SL, Weinberg AD, English M, Huston G. 1990.. IL-4 directs the development of Th2-like helper effectors. . J. Immunol. 145::3796–806
     [Crossref] [Google Scholar]
  65. 65.
    Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. 1990.. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. . J. Exp. Med. 172::921–29
     [Crossref] [Google Scholar]
  66. 66.
    Murphy KM, Heimberger AB, Loh DY. 1990.. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. . Science 250::1720–23
     [Crossref] [Google Scholar]
  67. 67.
    O'Garra A, Murphy KM. 2009.. From IL-10 to IL-12: how pathogens and their products stimulate APCs to induce TH1 development. . Nat. Immunol. 10::929–32
     [Crossref] [Google Scholar]
  68. 68.
    Hsieh CS, Heimberger AB, Gold JS, O'Garra A, Murphy KM. 1992.. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an αβ T-cell-receptor transgenic system. . PNAS 89::6065–69
     [Crossref] [Google Scholar]
  69. 69.
    Janeway CA Jr. 1989.. Approaching the asymptote? Evolution and revolution in immunology. . Cold Spring Harb. Symp. Quant. Biol. 54:(Part 1):1–13
     [Crossref] [Google Scholar]
  70. 70.
    Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM. 1993.. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. . Science 260::547–49
     [Crossref] [Google Scholar]
  71. 71.
    Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospisil M, et al. 1991.. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. . J. Exp. Med. 173::869–79
     [Crossref] [Google Scholar]
  72. 72.
    Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, et al. 1991.. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. . J. Immunol. 146::3074–81
     [Crossref] [Google Scholar]
  73. 73.
    Macatonia SE, Hsieh CS, Murphy KM, O'Garra A. 1993.. Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN-γ production is IFN-γ-dependent. . Int. Immunol. 5::1119–28
     [Crossref] [Google Scholar]
  74. 74.
    Murphy EE, Terres G, Macatonia SE, Hsieh CS, Mattson J, et al. 1994.. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. . J. Exp. Med. 180::223–31
     [Crossref] [Google Scholar]
  75. 75.
    Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, et al. 1995.. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. . J. Immunol. 154::5071–79
     [Crossref] [Google Scholar]
  76. 76.
    Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. 1996.. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. . J. Exp. Med. 184::747–52
     [Crossref] [Google Scholar]
  77. 77.
    Koch F, Stanzl U, Jennewein P, Janke K, Heufler C, et al. 1996.. High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. . J. Exp. Med. 184::741–46
     [Crossref] [Google Scholar]
  78. 78.
    Schulz O, Edwards AD, Schito M, Aliberti J, Manickasingham S, et al. 2000.. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. . Immunity 13::453–62
     [Crossref] [Google Scholar]
  79. 79.
    Castro AG, Neighbors M, Hurst SD, Zonin F, Silva RA, et al. 2000.. Anti-interleukin 10 receptor monoclonal antibody is an adjuvant for T helper cell type 1 responses to soluble antigen only in the presence of lipopolysaccharide. . J. Exp. Med. 192::1529–34
     [Crossref] [Google Scholar]
  80. 80.
    Shibuya K, Robinson D, Zonin F, Hartley SB, Macatonia SE, et al. 1998.. IL-1α and TNF-α are required for IL-12–induced development of Th1 cells producing high levels of IFN-γ in BALB/c but not C57BL/6 mice. . J. Immunol. 160::1708–16
     [Crossref] [Google Scholar]
  81. 81.
    Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, et al. 1995.. Cloning of a new cytokine that induces IFN-γ production by T cells. . Nature 378::88–91
     [Crossref] [Google Scholar]
  82. 82.
    Bazan JF, Timans JC, Kastelein RA. 1996.. A newly defined interleukin-1?. Nature 379::591
     [Crossref] [Google Scholar]
  83. 83.
    Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, et al. 1997.. IGIF does not drive Th1 development but synergizes with IL-12 for interferon-γ production and activates IRAK and NFκB. . Immunity 7::571–81
     [Crossref] [Google Scholar]
  84. 84.
    Brieland JK, Jackson C, Hurst S, Loebenberg D, Muchamuel T, et al. 2000.. Immunomodulatory role of endogenous interleukin-18 in gamma interferon-mediated resolution of replicative Legionella pneumophila lung infection. . Infect. Immun. 68::6567–73
     [Crossref] [Google Scholar]
  85. 85.
    Neighbors M, Xu X, Barrat FJ, Ruuls SR, Churakova T, et al. 2001.. A critical role for interleukin 18 in primary and memory effector responses to Listeria monocytogenes that extends beyond its effects on interferon γ production. . J. Exp. Med. 194::343–54
     [Crossref] [Google Scholar]
  86. 86.
    Szabo SJ, Jacobson NG, Dighe AS, Gubler U, Murphy KM. 1995.. Developmental commitment to the Th2 lineage by extinction of IL-12 signaling. . Immunity 2::665–75
     [Crossref] [Google Scholar]
  87. 87.
    Murphy E, Shibuya K, Hosken N, Openshaw P, Maino V, et al. 1996.. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. . J. Exp. Med. 183::901–13
     [Crossref] [Google Scholar]
  88. 88.
    Openshaw P, Murphy EE, Hosken NA, Maino V, Davis K, et al. 1995.. Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations. . J. Exp. Med. 182::1357–67
     [Crossref] [Google Scholar]
  89. 89.
    Coffman RL, Mocci S, O'Garra A. 1999.. The stability and reversibility of Th1 and Th2 populations. . In Redirection of Th1 and Th2 Responses, ed. RL Coffman, S Romagnani , pp. 1–12. Curr. Top. Microbiol. Immunol. 238 . Berlin:: Springer
     [Google Scholar]
  90. 90.
    Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. 2003.. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. . Nat. Immunol. 4::78–86
     [Crossref] [Google Scholar]
  91. 91.
    O'Garra A. 1998.. Cytokines induce the development of functionally heterogeneous T helper cell subsets. . Immunity 8::275–83
     [Crossref] [Google Scholar]
  92. 92.
    Arai N, Lee HJ, Ferber I, Kurata H, O'Garra A. 1999.. Multiple levels of regulation of Th2 cytokine gene expression. . Cold Spring Harb. Symp. Quant. Biol. 64::589–98
     [Crossref] [Google Scholar]
  93. 93.
    Ferber IA, Lee HJ, Zonin F, Heath V, Mui A, et al. 1999.. GATA-3 significantly downregulates IFN-γ production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. . Clin. Immunol. 91::134–44
     [Crossref] [Google Scholar]
  94. 94.
    Heath VL, Kurata H, Lee HJ, Arai N, O'Garra A. 2002.. Checkpoints in the regulation of T helper 1 responses. . In The Interface Between Innate and Acquired Immunity, ed. MD Cooper, H Koprowski , pp. 23–39. Curr. Top. Microbiol. Immunol. 266 . Berlin:: Springer
     [Google Scholar]
  95. 95.
    Lee HJ, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, et al. 2000.. GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. . J. Exp. Med. 192::105–15
     [Crossref] [Google Scholar]
  96. 96.
    O'Garra A, Arai N. 2000.. The molecular basis of T helper 1 and T helper 2 cell differentiation. . Trends Cell Biol. 10::542–50
     [Crossref] [Google Scholar]
  97. 97.
    Bacchetta R, Bigler M, Touraine JL, Parkman R, Tovo PA, et al. 1994.. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. . J. Exp. Med. 179::493–502
     [Crossref] [Google Scholar]
  98. 98.
    Levings MK, Roncarolo MG. 2000.. T-regulatory 1 cells: a novel subset of CD4 T cells with immunoregulatory properties. . J. Allergy Clin. Immunol. 106::S109–12
     [Crossref] [Google Scholar]
  99. 99.
    Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, et al. 2002.. In vitro generation of interleukin 10–producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)– and Th2-inducing cytokines. . J. Exp. Med. 195::603–16
     [Crossref] [Google Scholar]
  100. 100.
    Vieira PL, Christensen JR, Minaee S, O'Neill EJ, Barrat FJ, et al. 2004.. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. . J. Immunol. 172::5986–93
     [Crossref] [Google Scholar]
  101. 101.
    Burkhart C, Liu GY, Anderton SM, Metzler B, Wraith DC. 1999.. Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. . Int. Immunol. 11::1625–34
     [Crossref] [Google Scholar]
  102. 102.
    Gabryšová L, Nicolson KS, Streeter HB, Verhagen J, Sabatos-Peyton CA, et al. 2009.. Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10–secreting Th1 cells. . J. Exp. Med. 206::1755–67
     [Crossref] [Google Scholar]
  103. 103.
    Hawrylowicz CM, O'Garra A. 2005.. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. . Nat. Rev. Immunol. 5::271–83
     [Crossref] [Google Scholar]
  104. 104.
    Saraiva M, O'Garra A. 2010.. The regulation of IL-10 production by immune cells. . Nat. Rev. Immunol. 10::170–81
     [Crossref] [Google Scholar]
  105. 105.
    WHO (World Health Organ.). 2024.. Global Tuberculosis Report 2021. Geneva:: WHO
     [Google Scholar]
  106. 106.
    Redford PS, Boonstra A, Read S, Pitt J, Graham C, et al. 2010.. Enhanced protection to Mycobacterium tuberculosis infection in IL-10-deficient mice is accompanied by early and enhanced Th1 responses in the lung. . Eur. J. Immunol. 40::2200–10
     [Crossref] [Google Scholar]
  107. 107.
    Redford PS, Murray PJ, O'Garra A. 2011.. The role of IL-10 in immune regulation during M. tuberculosis infection. . Mucosal Immunol. 4::261–70
     [Crossref] [Google Scholar]
  108. 108.
    Casanova JL, Abel L. 2002.. Genetic dissection of immunity to mycobacteria: the human model. . Annu. Rev. Immunol. 20::581–620
     [Crossref] [Google Scholar]
  109. 109.
    Cooper AM, Roberts AD, Rhoades ER, Callahan JE, Getzy DM, Orme IM. 1995.. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. . Immunology 84::423–32
     [Google Scholar]
  110. 110.
    Flynn JL, Chan J. 2001.. Immunology of tuberculosis. . Annu. Rev. Immunol. 19::93–129
     [Crossref] [Google Scholar]
  111. 111.
    Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, et al. 2001.. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. . N. Engl. J. Med. 345::1098–104
     [Crossref] [Google Scholar]
  112. 112.
    North RJ, Jung YJ. 2004.. Immunity to tuberculosis. . Annu. Rev. Immunol. 22::599–623
     [Crossref] [Google Scholar]
  113. 113.
    Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, et al. 2003.. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. . J. Exp. Med. 197::711–23
     [Crossref] [Google Scholar]
  114. 114.
    Chaussabel D. 2004.. Biomedical literature mining: challenges and solutions in the ‘omics’ era. . Am. J. Pharmacogenom. 4::383–93
     [Crossref] [Google Scholar]
  115. 115.
    Berry MP, Graham CM, McNab FW, Xu Z, Bloch SA, et al. 2010.. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. . Nature 466::973–77
     [Crossref] [Google Scholar]
  116. 116.
    Bloom CI, Graham CM, Berry MP, Wilkinson KA, Oni T, et al. 2012.. Detectable changes in the blood transcriptome are present after two weeks of antituberculosis therapy. . PLOS ONE 7::e46191
     [Crossref] [Google Scholar]
  117. 117.
    Bloom CI, Graham CM, Berry MP, Rozakeas F, Redford PS, et al. 2013.. Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers. . PLOS ONE 8::e70630
     [Crossref] [Google Scholar]
  118. 118.
    Blankley S, Berry MP, Graham CM, Bloom CI, Lipman M, O'Garra A. 2014.. The application of transcriptional blood signatures to enhance our understanding of the host response to infection: the example of tuberculosis. . Philos. Trans. R. Soc. B 369::20130427
     [Crossref] [Google Scholar]
  119. 119.
    Blankley S, Graham CM, Levin J, Turner J, Berry MP, et al. 2016.. A 380-gene meta-signature of active tuberculosis compared with healthy controls. . Eur. Respir. J. 47::1873–76
     [Crossref] [Google Scholar]
  120. 120.
    Blankley S, Graham CM, Turner J, Berry MP, Bloom CI, et al. 2016.. The transcriptional signature of active tuberculosis reflects symptom status in extra-pulmonary and pulmonary tuberculosis. . PLOS ONE 11::e0162220
     [Crossref] [Google Scholar]
  121. 121.
    Singhania A, Verma R, Graham CM, Lee J, Tran T, et al. 2018.. A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection. . Nat. Commun. 9::2308
     [Crossref] [Google Scholar]
  122. 122.
    Singhania A, Wilkinson RJ, Rodrigue M, Haldar P, O'Garra A. 2018.. The value of transcriptomics in advancing knowledge of the immune response and diagnosis in tuberculosis. . Nat. Immunol. 19::1159–68
     [Crossref] [Google Scholar]
  123. 123.
    Tabone O, Verma R, Singhania A, Chakravarty P, Branchett WJ, et al. 2021.. Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis. . J. Exp. Med. 218::e20210915
     [Crossref] [Google Scholar]
  124. 124.
    Moreira-Teixeira L, Mayer-Barber K, Sher A, O'Garra A. 2018.. Type I interferons in tuberculosis: foe and occasionally friend. . J. Exp. Med. 215::1273–85
     [Crossref] [Google Scholar]
  125. 125.
    O'Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MPR. 2013.. The immune response in tuberculosis. . Annu. Rev. Immunol. 31::475–527
     [Crossref] [Google Scholar]
  126. 126.
    Mayer-Barber KD, Andrade BB, Barber DL, Hieny S, Feng CG, et al. 2011.. Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. . Immunity 35::1023–34
     [Crossref] [Google Scholar]
  127. 127.
    Mayer-Barber KD, Andrade BB, Oland SD, Amaral EP, Barber DL, et al. 2014.. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. . Nature 511::99–103
     [Crossref] [Google Scholar]
  128. 128.
    McNab FW, Ewbank J, Howes A, Moreira-Teixeira L, Martirosyan A, et al. 2014.. Type I IFN induces IL-10 production in an IL-27–independent manner and blocks responsiveness to IFN-γ for production of IL-12 and bacterial killing in Mycobacterium tuberculosis–infected macrophages. . J. Immunol. 193::3600–12
     [Crossref] [Google Scholar]
  129. 129.
    McNab FW, Ewbank J, Rajsbaum R, Stavropoulos E, Martirosyan A, et al. 2013.. TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production. . J. Immunol. 191::1732–43
     [Crossref] [Google Scholar]
  130. 130.
    Moreira-Teixeira L, Sousa J, McNab FW, Torrado E, Cardoso F, et al. 2016.. Type I IFN inhibits alternative macrophage activation during Mycobacterium tuberculosis infection and leads to enhanced protection in the absence of IFN-γ signaling. . J. Immunol. 197::4714–26
     [Crossref] [Google Scholar]
  131. 131.
    Moreira-Teixeira L, Stimpson PJ, Stavropoulos E, Hadebe S, Chakravarty P, et al. 2020.. Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing lung neutrophil-mediated inflammation and NETosis. . Nat. Commun. 11::5566
     [Crossref] [Google Scholar]
  132. 132.
    Kramnik I, Dietrich WF, Demant P, Bloom BR. 2000.. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. . PNAS 97::8560–65
     [Crossref] [Google Scholar]
  133. 133.
    Moreira-Teixeira L, Tabone O, Graham CM, Singhania A, Stavropoulos E, et al. 2020.. Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis. . Nat. Immunol. 21::464–76
     [Crossref] [Google Scholar]
  134. 134.
    Boonstra A, Rajsbaum R, Holman M, Marques R, Asselin-Paturel C, et al. 2006.. Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals. . J. Immunol. 177::7551–58
     [Crossref] [Google Scholar]
  135. 135.
    Howes A, Taubert C, Blankley S, Spink N, Wu X, et al. 2016.. Differential production of type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages. . J. Immunol. 197::2838–53
     [Crossref] [Google Scholar]
  136. 136.
    Kaiser F, Cook D, Papoutsopoulou S, Rajsbaum R, Wu X, et al. 2009.. TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells. . J. Exp. Med. 206::1863–71
     [Crossref] [Google Scholar]
  137. 137.
    O'Garra A, Vieira P. 2007.. TH1 cells control themselves by producing interleukin-10. . Nat. Rev. Immunol. 7::425–28
     [Crossref] [Google Scholar]
  138. 138.
    Ouyang W, O'Garra A. 2019.. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. . Immunity 50::871–91
     [Crossref] [Google Scholar]
  139. 139.
    Saraiva M, Vieira P, O'Garra A. 2020.. Biology and therapeutic potential of interleukin-10. . J. Exp. Med. 217::e20190418
     [Crossref] [Google Scholar]
  140. 140.
    Anderson CF, Oukka M, Kuchroo VJ, Sacks D. 2007.. CD4+CD25−Foxp3− Th1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis. . J. Exp. Med. 204::285–97
     [Crossref] [Google Scholar]
  141. 141.
    Freitas do Rosário AP, Lamb T, Spence P, Stephens R, Lang A, et al. 2012.. IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. . J. Immunol. 188::1178–90
     [Crossref] [Google Scholar]
  142. 142.
    Freitas do Rosário AP, Langhorne J. 2012.. T cell-derived IL-10 and its impact on the regulation of host responses during malaria. . Int. J. Parasitol. 42::549–55
     [Crossref] [Google Scholar]
  143. 143.
    Jankovic D, Kugler DG, Sher A. 2010.. IL-10 production by CD4+ effector T cells: a mechanism for self-regulation. . Mucosal Immunol. 3::239–46
     [Crossref] [Google Scholar]
  144. 144.
    Jankovic D, Kullberg MC, Feng CG, Goldszmid RS, Collazo CM, et al. 2007.. Conventional T-bet+Foxp3− Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. . J. Exp. Med. 204::273–83
     [Crossref] [Google Scholar]
  145. 145.
    Moreira-Teixeira L, Redford PS, Stavropoulos E, Ghilardi N, Maynard CL, et al. 2017.. T cell–derived IL-10 impairs host resistance to Mycobacterium tuberculosis infection. . J. Immunol. 199::613–23
     [Crossref] [Google Scholar]
  146. 146.
    Roers A, Siewe L, Strittmatter E, Deckert M, Schluter D, et al. 2004.. T cell–specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. . J. Exp. Med. 200::1289–97
     [Crossref] [Google Scholar]
  147. 147.
    Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, O'Garra A. 2009.. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. . Immunity 31::209–19
     [Crossref] [Google Scholar]
  148. 148.
    Gabryšová L, Howes A, Saraiva M, O'Garra A. 2014.. The regulation of IL-10 expression. . In Interleukin-10 in Health and Disease, ed. S Fillatreau, A O'Garra , pp. 157–90. Curr. Top. Microbiol. Immunol. 380 . Berlin:: Springer
     [Google Scholar]
  149. 149.
    Gabryšová L, Alvarez-Martinez M, Luisier R, Cox LS, Sodenkamp J, et al. 2018.. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells. . Nat. Immunol. 19::497–507
     [Crossref] [Google Scholar]
  150. 150.
    Neumann C, Scheffold A, Rutz S. 2019.. Functions and regulation of T cell-derived interleukin-10. . Semin. Immunol. 44::101344
     [Crossref] [Google Scholar]
  151. 151.
    Cox LS, Alvarez-Martinez M, Wu X, Gabryšová L, Luisier R, et al. 2023.. Blimp-1 and c-Maf regulate Il10 and negatively regulate common and unique proinflammatory gene networks in IL-12 plus IL-27-driven T helper-1 cells. . Wellcome Open Res. 8::403. https://wellcomeopenresearch.org/articles/8-403/v2
    [Crossref] [Google Scholar]
  152. 152.
    Zhang H, Madi A, Yosef N, Chihara N, Awasthi A, et al. 2020.. An IL-27-driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets. . Cell Rep. 33::108433
     [Crossref] [Google Scholar]
  153. 153.
    Alvarez-Martinez M, Cox LS, Pearson CF, Branchett WJ, Chakravarty P, et al. 2024.. Blimp-1 and c-Maf regulate immune gene networks to protect against distinct pathways of pathobiont-induced colitis. . Nat. Immunol. 25::886–901
     [Crossref] [Google Scholar]
  154. 154.
    Branchett WJ, O'Garra A. 2004.. c-MAF and BLIMP-1 inhibit pathobiont-induced colitis by common and distinct immune pathways. . Nat. Immunol. 25::737–38
     [Google Scholar]
/content/journals/10.1146/annurev-immunol-010824-041601
Loading
From Cytokines to Tuberculosis and Back: My Journey to Understanding the Immune Response to Infection
Annual Review of Immunology 43, 1 (2025); https://doi.org/10.1146/annurev-immunol-010824-041601
/content/journals/10.1146/annurev-immunol-010824-041601
/content/journals/10.1146/annurev-immunol-010824-041601
Loading

Data & Media loading...

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error