Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-κB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-κB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to na？ve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-κB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis–fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-κB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-κB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.
References
[1]
Servin AL (2004) Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens. FEMS Microbiol Rev 28: 405–40.
[2]
Corr SC, Li Y, Riedel CU, O'Toole PW, Hill C, et al. (2007) Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proc Natl Acad Sci U S A 104: 7617–21.
[3]
Gill HS (2003) Probiotics to enhance anti-infective defences in the gastrointestinal tract. Best Pract Res Clin Gastroenterol 17: 755–73.
[4]
Kitano H, Oda K (2006) Robustness trade-offs and host-microbial symbiosis in the immune system. Mol Syst Biol 2: 2006.0022.
[5]
Belkaid Y, Rouse BT (2005) Natural regulatory T cells in infectious disease. Nature Immunol 6: 353–360.
[6]
Karim M, Kingsley CI, Bushell AR, Sawitzki BS, Wood KJ (2004) Alloantigen-induced CD25+CD4+ regulatory T cells can develop in vivo from CD25？CD4+ precursors in a thymus-independent process. J Immunol 172: 923–928.
[7]
Chen W, Jin W, Hardegen N, Lei KJ, Li L, et al. (2003) Conversion of peripheral CD4+CD25？ naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med 198: 1875–1886.
[8]
Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, et al. (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204: 1775–1785.
[9]
Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV, Hall J, Sun CM, et al. (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204: 1757–64.
[10]
Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M (2005) Probiotics Ameliorate Recurrent Th1-Mediated Murine Colitis by Inducing IL-10 and IL-10-Dependent TGF-β Bearing Regulatory Cells. J Immunol 174: 3237–3246.
[11]
Collier-Hyams LS, Neish AS (2005) Innate immune relationship between commensal flora and the mammalian intestinal epithelium. Cell Mol Life Sci 62: 1339–1348.
[12]
Collier-Hyams LS, Zeng H, Sun J, Tomlinson AD, Bao ZQ, et al. (2002) Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-kappa B pathway. J Immunol 2002 169: 2846–2850.
[13]
Kelly D, Campbell JI, King TP, Grant G, Jansson EA, et al. (2004) Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol 5: 104–112.
[14]
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor +-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151–1164.
[15]
Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, et al. (1999) Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 162: 5317–5326.
[16]
Kohm AP, Carpentier PA, Anger HA, Miller SD (2002) Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169: 4712–4716.
[17]
Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170: 3939–3943.
[18]
Kullberg MC, Jankovic D, Gorelick PL, Caspar P, Letterio JJ, et al. (2002) Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J Exp Med 196: 505–515.
[19]
Morgan ME, Sutmuller RP, Witteveen HJ, van Duivenvoorde LM, Zanelli E, et al. (2003) CD25+ cell depletion hastens the onset of severe disease in collagen induced arthritis. Arthritis Rheum 48: 1452–1460.
[20]
Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, et al. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431–440.
[21]
Jaffar Z, Sivakuru T, Roberts K (2004) CD4+CD25+ T cells regulate airway eosinophilic inflammation by modulating the Th2 cell phenotype. J Immunol 172: 3842–3849.
[22]
Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99: 3493–3499.
[23]
van Maurik A, Herber M, Wood KJ, Jones ND (2002) Cutting edge: CD4+CD25+ alloantigen-specific immunoregulatory cells that can prevent CD8+ T cell-mediated graft rejection: implications for anti-CD154 immunotherapy. J Immunol 169: 5401–5404.
[24]
Sheil B, McCarthy J, O'Mahony L, Bennett MW, Ryan P, et al. (2004) Is the mucosal route of administration essential for probiotic function? Subcutaneous administration is associated with attenuation of murine colitis and arthritis. Gut 53: 694–700.
[25]
Forsythe P, Inman MD, Bienenstock J (2007) Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice. Am J Respir Crit Care Med 175: 561–569.
[26]
McCarthy J, O'Mahony L, O'Callaghan L, Sheil B, Vaughan EE, et al. (2003) Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut 52: 975–980.
[27]
O'Mahony L, Feeney M, O'Halloran S, Murphy L, Kiely B, et al. (2001) Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice. Alim Pharmacol Ther 15: 1219–1225.
[28]
Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci USA 104: 19446–19451.
[29]
Taams LS, van Amelsfort JM, Tiemessen MM, Jacobs KM, de Jong EC, et al. (2005) Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol 66: 222–230.
[30]
Young JW, Merad M, Hart DN (2007) Dendritic cells in transplantation and immune-based therapies. Biol Blood Marrow Transplant 13: 23–32.
[31]
Amati L, Pepe M, Passeri ME, Mastronardi ML, Jirillo E, et al. (2006) Toll-like receptor signaling mechanisms involved in dendritic cell activation: potential therapeutic control of T cell polarization. Curr Pharm Des 12: 4247–4254.
[32]
Kelsall BL (2008) Innate and adaptive mechanisms to control pathological intestinal inflammation. J Pathol 214: 242–259.
[33]
O'Mahony L, O'Callaghan L, McCarthy J, Shilling D, Scully P, et al. (2006) Differential cytokine response from dendritic cells to commensal and pathogenic bacteria in different lymphoid compartments in humans. Am J Physiol Gastrointest Liver Physiol 290: G839–G845.
[34]
Smits HH, Engering A, Van der Kleij D, De Jong EC, Schipper K, et al. (2005) Selective probiotic bacteria induce IL-10–producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin. J Allergy Clin Immunol 115: 1260–1267.
[35]
Niers LEM, Timmermanw HM, Rijkersw GT, van Bleekw GM, van Udenw NOP, et al. (2005) Identification of strong interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines. Clin Exp Allergy 35: 1481–1489.
[36]
Hawiger J (2001) Innate immunity and inflammation: a transcriptional paradigm. Immunol Res 23: 99–109.
[37]
O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, et al. (2005) Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 128: 541–551.
[38]
Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, et al. (2006) Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 101: 1581–1590.
[39]
Riesenberg-Wilmes MR, Bearson B, Foster JW, Curtis R (1996) Role of the acid tolerance response in virulence of Salmonella typhimurium. Infect Immun 64: 1085–1092.
[40]
Riesenberg-Wilmes MR, Bearson B, Foster JW, Curtis R (1997) An altered rpoS allele contributes to the avirulence of Salmonella typhimurium LT2. Infect Immun 65: 203–210.
[41]
O'Mahony L, Kenneally P, O'Donoghue M, Kiely B, Shanahan F, Collins JK (2002) Multi-organism comparison of probiotic performance in a murine model of Salmonella typhimurimum infection. Gastroenterology 122: A458–A458.
