Mast Cells and Immunoregulation/Immunomodulation

  • Mindy Tsai
  • Michele Grimbaldeston
  • Stephen J. Galli
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 716)


Mast cells often represent one of the first cells of the immune system to interact with environmental antigens, invading pathogens or environmentally-derived toxins. Mast cells also can undergo alterations in phenotype, anatomic distribution and numbers during innate or adaptive immune responses. In addition to their well-known roles as effector cells during IgE- and antigen-induced allergic reactions, mast cells can be activated by many other signals, including some that are derived directly from pathogens or which are generated during innate or adaptive immune responses. Mast cells also express many costimulatory molecules with immunoregulatory activities and can secrete many products that can positively or negatively regulate immune responses. In this chapter, we describe mouse models used for analyzing mast-cell function in vivo and illustrate how such models have been used to identify positive or negative immunomodulatory roles for mast cells during specific innate or adaptive immune responses. We also briefly describe some of the mast-cell functions, products and surface receptors that have the potential to permit mast cells to promote or suppress immune responses that can either enhance host defense or contribute to disease.


Mast Cell Mast Cell Activation Human Mast Cell Mouse Mast Cell Mast Cell Protease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kitamura Y. Heterogeneity of mast cells and phenotypic change between subpopulations. Annu Rev Immunol 1989; 7:59–76.PubMedCrossRefGoogle Scholar
  2. 2.
    Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev 1997; 77:1033–1079.PubMedGoogle Scholar
  3. 3.
    Kawakami T, Galli SJ. Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol 2002; 2:773–786.PubMedCrossRefGoogle Scholar
  4. 4.
    Ryan JJ, Kashyap M, Bailey D et al. Mast cell homeostasis: a fundamental aspect of allergic disease. Crit Rev Immunol 2007; 27:15–32.PubMedGoogle Scholar
  5. 5.
    Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol 2004; 4:787–799.PubMedCrossRefGoogle Scholar
  6. 6.
    Galli SJ, Kalesnikoff J, Grimbaldeston MA et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005; 23:749–786.PubMedCrossRefGoogle Scholar
  7. 7.
    Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nat Immunol 2005; 6:135–142.PubMedCrossRefGoogle Scholar
  8. 8.
    Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol 2010; 10:440–452.PubMedCrossRefGoogle Scholar
  9. 9.
    Moon TC, St Laurent CD, Morris KE et al. Advances inmast cell biology: new understanding of heterogeneity and function. Mucosal Immunol 2010; 3:111–128.PubMedCrossRefGoogle Scholar
  10. 10.
    Grimbaldeston MA, Metz M, Yu M et al. Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses. Curr Opin Immunol 2006; 18:751–760.PubMedCrossRefGoogle Scholar
  11. 11.
    Dawicki W, Marshall JS. New and emerging roles for mast cells in host defence. Curr Opin Immunol 2007; 19:31–38.PubMedCrossRefGoogle Scholar
  12. 12.
    Sayed BA, Brown MA. Mast cells as modulators of T-cell responses. Immunol Rev 2007; 217:53–64.PubMedCrossRefGoogle Scholar
  13. 13.
    Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 2008; 8:478–486.PubMedCrossRefGoogle Scholar
  14. 14.
    Mekori YA, Metcalfe DD. Mast cells in innate immunity. Immunol Rev 2000; 173:131–140.PubMedCrossRefGoogle Scholar
  15. 15.
    Malaviya R, Abraham SN. Mast cell modulation of immune responses to bacteria. Immunol Rev 2001; 179:16–24.PubMedCrossRefGoogle Scholar
  16. 16.
    Sayed BA, Christy A, Quirion MR et al. The master switch: the role of mast cells in autoimmunity and tolerance. Annu Rev Immunol 2008; 26:705–739.PubMedCrossRefGoogle Scholar
  17. 17.
    Maurer M et al. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 2004; 432:512–516.PubMedCrossRefGoogle Scholar
  18. 18.
    Metz M, Piliponsky AM, Chen CC et al. Mast cells can enhance resistance to snake and honeybee venoms. Science 2006; 313:526–530.PubMedCrossRefGoogle Scholar
  19. 19.
    Piliponsky AM, Chen CC, Nishimura T et al. Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis. Nat Med 2008; 14:392–398.PubMedCrossRefGoogle Scholar
  20. 20.
    Schneider LA, Schlenner SM, Feyerabend TB et al. Molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin. J Exp Med 2007; 204:2629–2639.PubMedCrossRefGoogle Scholar
  21. 21.
    Brown JM, Wilson TM, Metcalfe DD. The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp Allergy 2008; 38:4–18.PubMedGoogle Scholar
  22. 22.
    Frandji P, Oskéritzian C, Cacaraci F et al. Antigen-dependent stimulation by bone marrow-derived mast cells of MHC class II-restricted T-cell hybridoma. J Immunol 1993; 151:6318–6328.PubMedGoogle Scholar
  23. 23.
    Hart PH, Grimbaldeston MA, Swift GJ et al. Dermal mast cells determine susceptibility to ultraviolet B-induced systemic suppression of contact hypersensitivity responses in mice. J Exp Med 1998; 187:2045–2053.PubMedCrossRefGoogle Scholar
  24. 24.
    Grimbaldeston MA, Nakae S, Kalesnikoff J et al. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat Immunol 2007; 8:1095–1104.PubMedCrossRefGoogle Scholar
  25. 25.
    Mills KH. Regulatory T-cells: friend or foe in immunity to infection? Nat Rev Immunol 2004; 4:841–855.PubMedCrossRefGoogle Scholar
  26. 26.
    Grimbaldeston MA, Chen CC, Piliponsky AM et al. Mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 2005; 167:835–848.PubMedCrossRefGoogle Scholar
  27. 27.
    Wolters PJ, Mallen-St Clair J, Lewis CC et al. Tissue-selective mast cell reconstitution and differential lung gene expression in mast cell-deficient KitW-sh/W-sh sash mice. Clin Exp Allergy 2005; 35:82–88.PubMedCrossRefGoogle Scholar
  28. 28.
    Nigrovic PA, Gray DH, Jones T et al. Genetic inversion in mast cell-deficient Wsh mice interrupts corin and manifests as hematopoietic and cardiac aberrancy. Am J Pathol 2008; 173:1693–1701.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou JS, Xing W, Friend DS et al. Mast cell deficiency in KitW-sh mice does not impair antibody-mediated arthritis. J Exp Med 2007; 204:2797–2802.PubMedCrossRefGoogle Scholar
  30. 30.
    Piliponsky AM, Chen CC, Grimbaldeston MA et al. Mast cell-derived TNF can exacerbate mortality during severe bacterial infections in C57BL/6-KitW-sh/W-sh mice. Am J Pathol 2010; 176:926–938.PubMedCrossRefGoogle Scholar
  31. 31.
    Feyerabend TB, Hausser H, Tietz A et al. Loss of histochemical identity in mast cells lacking carboxypeptidase A. Mol Cell Biol 2005; 25:6199–6210.PubMedCrossRefGoogle Scholar
  32. 32.
    Knight PA, Wright SH, Lawrence CE et al. Delayed expulsion of the nematode Trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase, mouse mast cell protease-1. J Exp Med 2000; 192:1849–1856.PubMedCrossRefGoogle Scholar
  33. 33.
    Pejler G, Abrink M, Ringvall M et al. Mast cell proteases. Adv Immunol 2007; 95:167–255.PubMedCrossRefGoogle Scholar
  34. 34.
    Thakurdas SM, Melicoff E, Sansores-Garcia L et al. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J Biol Chem 2007; 282:20809–20815.PubMedCrossRefGoogle Scholar
  35. 35.
    Musch W, Wege AK, Mannel DN et al. Generation and characterization of alpha-chymase-Cre transgenic mice. Genesis 2008; 46:163–166.PubMedCrossRefGoogle Scholar
  36. 36.
    Scholten J, Hartmann K, Gerbaulet A et al. Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res 2008; 17:307–315.PubMedCrossRefGoogle Scholar
  37. 37.
    Feyerabend TB, Terszowski G, Tietz A et al. Deletion of Notchl converts pro-T cells to dendritic cells and promotes thymic B-cells by cell-extrinsic and cell-intrinsic mechanisms. Immunity 2009; 30:67–79.PubMedCrossRefGoogle Scholar
  38. 38.
    Newlands GF, Miller HR, MacKellar A et al. Stem cell factor contributes to intestinal mucosal mast cell hyperplasia in rats infected with Nippostrongylus brasiliensis or Trichinella spiralis, but anti-stem cell factortreatment decreases parasite eggproductionduringN. brasiliensis infection. Blood 1995; 86:1968–1976.PubMedGoogle Scholar
  39. 39.
    Brandt EB, Strait RT, Hershko D et al. Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest 2003; 112:1666–1677.PubMedGoogle Scholar
  40. 40.
    Gekara NO, Weiss S. Mast cells initiate early anti-Listeria host defences. Cell Microbiol 2008; 10:225–236.PubMedGoogle Scholar
  41. 41.
    Dietrich N, Rohde M, Geffers R et al. Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proc Natl Acad Sci USA 2010; 107:8748–8753.PubMedCrossRefGoogle Scholar
  42. 42.
    Soucek L, Lawlor ER, Soto D et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 2007; 13:1211–1218.PubMedCrossRefGoogle Scholar
  43. 43.
    Sun J, Sukhova GK, Yang M et al. Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest 2007; 117:3359–3368.PubMedCrossRefGoogle Scholar
  44. 44.
    Arumugam T, Ramachandran V, Logsdon CD. Effect of cromolyn on S100P interactions with RAGE and pancreatic cancer growth and invasion in mouse models. J Natl Cancer Inst 2006; 98:1806–1818.PubMedCrossRefGoogle Scholar
  45. 45.
    Norris AA. Pharmacology of sodium cromoglycate. Clin Exp Allergy 26 Suppl 1996; 4:5–7.CrossRefGoogle Scholar
  46. 46.
    Blank U, Rivera J. The ins and outs of IgE-dependentmast-cellexocytosis. Trends Immunol 2004; 25:266–273.PubMedCrossRefGoogle Scholar
  47. 47.
    Gilfillan AM, Tkaczyk C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 2006; 6:218–230.PubMedCrossRefGoogle Scholar
  48. 48.
    Metcalfe DD, Peavy RD, Gilfillan AM. Mechanisms of mast cell signaling in anaphylaxis. J Allergy Clin Immunol 2009; 124:639–646; quiz 647–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Rivera J, Gilfillan AM. Molecularregulation of mast cell activation. J Allergy Clin Immunol 2006; 117:1214–1225.PubMedCrossRefGoogle Scholar
  50. 50.
    Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol 2008; 9:1215–1223.PubMedCrossRefGoogle Scholar
  51. 51.
    Gonzalez-Espinosa C, Odom S, Olivera A et al. Preferential signaling and induction of allergy-promoting lymphokines upon weak stimulation of the high affinity IgE receptor on mast cells. J Exp Med 2003; 197:1453–1465.PubMedCrossRefGoogle Scholar
  52. 52.
    Chong HJ, Andrew Bouton L, Bailey DP et al. IL-4 selectively enhances FcgammaRIII expression and signaling on mouse mast cells. Cell Immunol 2003; 224:65–73.PubMedCrossRefGoogle Scholar
  53. 53.
    Andreu P, Johansson M, Affara NI et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 2010; 17:121–134.PubMedCrossRefGoogle Scholar
  54. 54.
    Okayama Y, Kirshenbaum AS, Metcalfe DD. Expression of a functional high-affinity IgG receptor, Fc gamma RI, on human mast cells: up-regulation by IFN-gamma. J Immunol 2000; 164:4332–4339.PubMedGoogle Scholar
  55. 55.
    Metz M, Grimbaldeston MA, Nakae S et al. Mast cells in the promotion and limitation of chronic inflammation. Immunol Rev 2007; 217:304–328.PubMedCrossRefGoogle Scholar
  56. 56.
    Heib V, Becker M, Warger T et al. Mast cells are crucial for early inflammation, migration of Langerhans cells and CTL responses following topical application of TLR7 ligand in mice. Blood 2007; 110:946–953.PubMedCrossRefGoogle Scholar
  57. 57.
    Heib V, Becker M, Taube C et al. Advances in the understanding of mast cell function. Br J Haematol 2008; 142:683–694.PubMedCrossRefGoogle Scholar
  58. 58.
    McLachlan JB, Shelburne CP, Hart JP et al. Mast cell activators: a new class of highly effective vaccine adjuvants. Nat Med 2008; 14:536–541.PubMedCrossRefGoogle Scholar
  59. 59.
    Hofmann AM, Abraham SN. New roles for mast cells in modulating allergic reactions and immunity against pathogens. Curr Opin Immunol 2009; 21:679–686.PubMedCrossRefGoogle Scholar
  60. 60.
    Kunder CA, St John AL, Li G et al. Mast cell-derived particles deliver peripheral signals to remote lymph nodes. J Exp Med 2009; 206:2455–2467.PubMedCrossRefGoogle Scholar
  61. 61.
    McKee AS, Munks MW, MacLeod MK et al. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol 2009; 183:4403–4414.PubMedCrossRefGoogle Scholar
  62. 62.
    Shelburne CP, Nakano H, St John AL et al. Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host Microbe 2009; 6:331–342.PubMedCrossRefGoogle Scholar
  63. 63.
    Kulka M, Alexopoulou L, Flavell RA et al. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol 2004; 114:174–182.PubMedCrossRefGoogle Scholar
  64. 64.
    Marshall JS, Jawdat DM. Mast cells in innate immunity. J Allergy Clin Immunol 2004; 114:21–27.PubMedCrossRefGoogle Scholar
  65. 65.
    Marshall JS, Brown MG, Pawankar R. in Allergy Frontiers, Vol 2: Classification and Pathomechanisms (ed. Pawankar R, Holgate ST, Rosenwasser LJ) 113–133 (Springer Japan, 2009).CrossRefGoogle Scholar
  66. 66.
    Supajatura V, Ushio H, Nakao A et al. Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest 2002; 109:1351–1359.PubMedGoogle Scholar
  67. 67.
    Orinska Z, Bulanova E, Budagian V et al. TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment. Blood 2005; 106:978–987.PubMedCrossRefGoogle Scholar
  68. 68.
    Wu L, Feng BS, He SH et al. Bacterial peptidoglycan breaks down intestinal tolerance via mast cell activation: the role of TLR2 and NOD2. Immunol Cell Biol 2007; 85:538–545.PubMedCrossRefGoogle Scholar
  69. 69.
    Feng BS, He SH, Zheng PY et al. Mast cells play a crucial role in Staphylococcus aureus peptidoglycan-induced diarrhea. Am J Pathol 2007; 171:537–547.PubMedCrossRefGoogle Scholar
  70. 70.
    Okumura S, Yuki K, Kobayashi R et al. Hyperexpression of NOD2 in intestinal mast cells of Crohn’s disease patients: preferential expression of inflammatory cell-recruiting molecules via NOD2 in mast cells. Clin Immunol 2009; 130:175–185.PubMedCrossRefGoogle Scholar
  71. 71.
    Nakamura Y, Kambe N, Saito M et al. Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria. J Exp Med 2009; 206:1037–1046.PubMedCrossRefGoogle Scholar
  72. 72.
    Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009; 27:229–265.PubMedCrossRefGoogle Scholar
  73. 73.
    Stutz A, Golenbock DT, Latz E. Inflammasomes: too big to miss. J Clin Invest 2009; 119:3502–3511.PubMedCrossRefGoogle Scholar
  74. 74.
    Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science 2010; 327:291–295.PubMedCrossRefGoogle Scholar
  75. 75.
    Gutzmer R, Diestel C, Mommert S et al. Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells. J Immunol 2005; 174:5224–5232.PubMedGoogle Scholar
  76. 76.
    Mazzoni A, Young HA, Spitzer JH et al. Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T-cell polarization. J Clin Invest 2001; 108:1865–1873.PubMedGoogle Scholar
  77. 77.
    Caron G, Delneste Y, Roelandts E et al. Histamine polarizes human dendritic cells into Th2 cell-promoting effector dendritic cells. J Immunol 2001; 167:3682–3686.PubMedGoogle Scholar
  78. 78.
    Mazzoni A, Leifer CA, Mullen GE et al. Cutting edge: histamine inhibits IFN-alpha release from plasmacytoid dendritic cells. J Immunol 2003; 170:2269–2273.PubMedGoogle Scholar
  79. 79.
    Kitawaki T, Kadowaki N, Sugimoto N et al. IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells. Int Immunol 2006; 18:1789–1799.PubMedCrossRefGoogle Scholar
  80. 80.
    Theiner G, Gessner A, Lutz MB. The mast cell mediator PGD2 suppresses IL-12 release by dendritic cells leading to Th2 polarized immune responses in vivo. Immunobiology 2006; 211:463–472.PubMedCrossRefGoogle Scholar
  81. 81.
    Kalinski P, Hilkens CM, Snijders A et al. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J. Immunol, 1997; 159, 28–35.PubMedGoogle Scholar
  82. 82.
    Mazzoni A, Siraganian RP, Leifer CA et al. Dendritic cell modulation by mast cells controls the Th1/Th2 balance in responding T-cells. J Immunol 2006; 177:3577–3581.PubMedGoogle Scholar
  83. 83.
    Gosset P, Bureau F, Angeli V et al. Prostaglandin D2 affects the maturation of human monocyte-derived dendritic cells: consequence on the polarization of naive Th cells. J Immunol 2003; 170:4943–4952.PubMedGoogle Scholar
  84. 84.
    Gosset P, Pichavant M, Faveeuw C et al. Prostaglandin D2 affects the differentiation and functions of human dendritic cells: impact on the T-cell response. Eur J Immunol 2005; 35:1491–1500.PubMedCrossRefGoogle Scholar
  85. 85.
    Del Prete A, Shao WH, Mitola S et al. Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function. Blood 2007; 109:626–631.PubMedCrossRefGoogle Scholar
  86. 86.
    Skokos D, Botros HG, Demeure C et al. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol 2003; 170:3037–3045.PubMedGoogle Scholar
  87. 87.
    Bryce PJ et al. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 2004; 20:381–392.PubMedCrossRefGoogle Scholar
  88. 88.
    Jawdat DM, Albert EJ, Rowden G et al. IgE-mediated mast cell activation induces Langerhans cell migration in vivo. J Immunol 2004; 173:5275–5282.PubMedGoogle Scholar
  89. 89.
    Suto H, Nakae S, Kakurai M et al. Mast cell-associated TNF promotes dendritic cell migration. J Immunol 2006; 176:4102–4112.PubMedGoogle Scholar
  90. 90.
    Jawdat DM, Rowden G, Marshall JS. Mast cells have a pivotal role in TNF-independent lymph node hypertrophy and the mobilization of Langerhans cells in response to bacterial peptidoglycan. J Immunol 2006; 177:1755–1762.PubMedGoogle Scholar
  91. 91.
    Dawicki W, Jawdat DW, Xu N et al. Mast cells, histamine and IL-6 regulate the selective influx of dendritic cell subsets into an inflamed lymph node. J Immunol 2010; 184:2116–2123.PubMedCrossRefGoogle Scholar
  92. 92.
    Mekori YA, Metcalfe DD. Mast cell-T-cell interactions. J Allergy Clin Immunol 1999; 104:517–523.PubMedCrossRefGoogle Scholar
  93. 93.
    Nakae S, Suto H, Kakurai M et al. Mast cells enhance T-cell activation: importance of mast cell-derived TNF. Proc Natl Acad Sci USA 2005; 102:6467–6472.PubMedCrossRefGoogle Scholar
  94. 94.
    Krishnaswamy G, Lakshman T, Miller AR et al. Multifunctional cytokine expression by human mast cells: regulation by T-cell membrane contact and glucocorticoids. J Interferon Cytokine Res 1997; 17:167–176.PubMedCrossRefGoogle Scholar
  95. 95.
    Bhattacharyya SP, Drucker I, Reshef T et al. Activated T-lymphocytes induce degranulation and cytokine production by human mast cells following cell-to-cell contact. J Leukoc Biol 1998; 63:337–341.PubMedGoogle Scholar
  96. 96.
    Inamura N, Mekori YA, Bhattacharyya SP et al. Induction and enhancement of Fc(epsilon)RI-dependent mast cell degranulation following coculture with activated T-cells: dependency on ICAM-1-and leukocyte function-associated antigen (LFA)-1-mediated heterotypic aggregation. J Immunol 1998; 160:4026–4033.PubMedGoogle Scholar
  97. 97.
    Baram D, Vaday GG, Salamon P et al. Human mast cells release metalloproteinase-9 on contact with activated T-cells: juxtacrine regulation by TNF-alpha. J Immunol 2001; 167:4008–4016.PubMedGoogle Scholar
  98. 98.
    Stopfer P, Marmel DN, Hehlgans T. Lymphotoxin-beta receptor activation by activated T-cells induces cytokine release from mouse bone marrow-derived mast cells. J Immunol 2004; 172:7459–7465.PubMedGoogle Scholar
  99. 99.
    Henz BM, Maurer M, Lippert U et al. Mast cells as initiators of immunity and host defense. Exp Dermatol 2001; 10:1–10.PubMedCrossRefGoogle Scholar
  100. 100.
    Fox CC, Jewell SD, Whitacre CC. Rat peritoneal mast cells present antigen to a PPD-specific T-cell line. Cell Immunol 1994; 158:253–264.PubMedCrossRefGoogle Scholar
  101. 101.
    Poncet P, Arock M, David B. MHC class II-dependent activation of CD4+ T-cell hybridomas by human mast cells through superantigen presentation. J Leukoc Biol 1999; 66:105–112.PubMedGoogle Scholar
  102. 102.
    Malaviya R, Twesten NJ, Ross EA et al. Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T-cells. J Immunol 1996; 156:1490–1496.PubMedGoogle Scholar
  103. 103.
    Stelekati E, Bahri R, D’Orlando O et al. Mast cell-mediated antigen presentation regulates CD8+ T-cell effector functions. Immunity 2009; 31:665–676.PubMedCrossRefGoogle Scholar
  104. 104.
    Gaudenzio N, Espagnolle N, Mars LT et al. Cell-cell cooperation at the Thelper cell/mast cell immunological synapse. Blood 2009; 114:4979–4988.PubMedCrossRefGoogle Scholar
  105. 105.
    Kambayashi T, Allenspach EJ, Chang JT et al. Inducible MHC class II expression by mast cells supports effector and regulatory T-cell activation. J Immunol 2009; 182:4686–4695.PubMedCrossRefGoogle Scholar
  106. 106.
    Frandji P, Tkaczyk C, Oskéritzian C et al. Presentation of soluble antigens by mast cells: upregulation by interleukin-4 and granulocyte/macrophage colony-stimulating factor and downregulation by interferon-gamma. Cell Immunol 1995; 163:37–46.PubMedCrossRefGoogle Scholar
  107. 107.
    Frandji P, Tkaczyk C, Oskeritzian C et al. Exogenous and endogenous antigens are differentially presented by mast cells to CD4+ T-lymphocytes. Eur J Immunol 1996; 26:2517–2528.PubMedCrossRefGoogle Scholar
  108. 108.
    Nakano N, Nishiyama C, Yagita H et al. Notch signaling confers antigen-presenting cell functions on mast cells. J Allergy Clin Immunol 2009; 123:74–81 e1.PubMedCrossRefGoogle Scholar
  109. 109.
    Lu LF, Lind EF, Gondek DC et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 2006; 442:997–1002.PubMedCrossRefGoogle Scholar
  110. 110.
    Skokos D, Le Panse S, Villa I et al. Mast cell-dependent B and T-lymphocyte activation is mediated by the secretion of immunologically active exosomes. J. Immunol. 2001; 166:868–876.PubMedGoogle Scholar
  111. 111.
    Kambayashi T, Baranski JD, Baker RG et al. Indirect involvement of allergen-captured mast cells in antigen presentation. Blood 2008; 111:1489–1496.PubMedCrossRefGoogle Scholar
  112. 112.
    Tkaczyk C, Viguier M, Boutin Y et al. Specific antigen targeting to surface IgE and IgG on mouse bone marrow-derived mast cells enhances efficiency of antigen presentation. Immunology 1998; 94:318–324.PubMedCrossRefGoogle Scholar
  113. 113.
    Tkaczyk C, Villa I, Peronet R et al. FcepsilonRI-mediated antigen endocytosis turns interferon-gamma-treated mouse mast cells from inefficient into potent antigen-presenting cells. Immunology 1999; 97:333–340.PubMedCrossRefGoogle Scholar
  114. 114.
    Kashiwakura J, Yokoi H, Saito H et al. T-cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T-cells: comparison of gene expression profiles between human tonsillar and lung-cultured mast cells. J. Immunol. 2004; 173:5247–5257.PubMedGoogle Scholar
  115. 115.
    Nakae S, Suto H, Iikura M et al. Mast cells enhance T-cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 2006; 176:2238–2248.PubMedGoogle Scholar
  116. 116.
    Xue L, Gyles SL, Wettey FR et al. Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells. J Immunol 2005; 175:6531–6536.PubMedGoogle Scholar
  117. 117.
    Jutel M, Watanabe T, Klunker S et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 2001; 413:420–425.PubMedCrossRefGoogle Scholar
  118. 118.
    Wang HW, Tedla N, Lloyd AR et al. Mast cell activation and migration to lymph nodes during induction of an immune response in mice. J. Clin. Invest. 1998; 102:1617–1626.PubMedCrossRefGoogle Scholar
  119. 119.
    Byrne SN, Limon-Flores AY, Ullrich SE. Mast cell migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression. J Immunol 2008; 180:4648–4655.PubMedGoogle Scholar
  120. 120.
    Tanzola MB, Robbie-Ryan M, Gutekunst CA et al. Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J Immunol 2003; 171:4385–4391.PubMedGoogle Scholar
  121. 121.
    Hochegger K, Siebenhaar F, Vielhauer V et al. Role of mast cells in experimental anti-glomerular basement membrane glomerulonephritis. Eur J Immunol 2005; 35:3074–3082.PubMedCrossRefGoogle Scholar
  122. 122.
    Gauchat JF, Henchoz S, Mazzei G et al. Induction of human IgE synthesis in B-cells by mast cells and basophils. Nature 1993; 365:340–343.PubMedCrossRefGoogle Scholar
  123. 123.
    Tkaczyk C, Frandji P, Botros HG et al. Mouse bone marrow-derived mast cells and mast cell lines constitutively produce B-cell growth and differentiation activities. J Immunol 1996; 157:1720–1728.PubMedGoogle Scholar
  124. 124.
    Merluzzi S, Frossi B, Gri G et al. Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells. Blood 2010; 115:2810–2817.PubMedCrossRefGoogle Scholar
  125. 125.
    Echtenacher B, Mannel DN, Hultner L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 1996; 381:75–77.PubMedCrossRefGoogle Scholar
  126. 126.
    Malaviya R, Ikeda T, Ross E et al. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature 1996; 381:77–80.PubMedCrossRefGoogle Scholar
  127. 127.
    Nakano, N. et al. Involvement of mast cells in IL-12/23 p40 production is essential for survival from polymicrobial infections. Blood 2007; 109:4846–4855.PubMedCrossRefGoogle Scholar
  128. 128.
    Sutherland RE, Olsen JS, McKinstry A et al. Mast cell IL-6 improves survival from Klebsiella pneumonia and sepsis by enhancing neutrophil killing. J Immunol 2008; 181:5598–5605.PubMedGoogle Scholar
  129. 129.
    Maurer M et al. The c-kit ligand, stem cell factor, can enhance innate immunity through effects on mast cells. J Exp Med 1998; 188:2343–2348.PubMedCrossRefGoogle Scholar
  130. 130.
    Prodeus AP, Zhou X, Maurer M et al. Impaired mast cell-dependent natural immunity in complement C3-deficient mice. Nature 1997; 390:172–175.PubMedCrossRefGoogle Scholar
  131. 131.
    Gommerman JL, Oh DY, Zhou X et al. A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: a potential mechanism for mast cell activation. J Immunol 2000; 165:6915–6921.PubMedGoogle Scholar
  132. 132.
    Kanamaru Y, Sumiyoshi K, Ushio H et al. Smad3 deficiency in mast cells provides efficient host protection against acute septic peritonitis. J Immunol 2005; 174:4193–3197.PubMedGoogle Scholar
  133. 133.
    Orinska Z, Maurer M, Mirghomizadeh F et al. IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nat Med 2007; 13:927–934.PubMedCrossRefGoogle Scholar
  134. 134.
    Metz M, Siebenhaar F, Maurer M. Mast cell functions in the innate skin immune system. Immunobiology 2008; 213:251–260.PubMedCrossRefGoogle Scholar
  135. 135.
    Sher A, Hein A, Moser G et al. Complement receptors promote the phagocytosis of bacteria by rat peritoneal mast cells. Lab Invest 1979; 41:490–499.PubMedGoogle Scholar
  136. 136.
    Malaviya R, Ross EA, MacGregor JI et al. Mast cell phagocytosis of FimH-expressing enterobacteria. J Immunol 1994; 152:1907–1914.PubMedGoogle Scholar
  137. 137.
    Di Nardo A, Vitiello A, Gallo RL. Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide. J Immunol 2003; 170:2274–2278.PubMedGoogle Scholar
  138. 138.
    von Köckritz-Blickwede M, Goldmann O et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 2008; 111:3070–3080.CrossRefGoogle Scholar
  139. 139.
    McLachlan JB, Hart JP, Pizzo SV et al. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nat Immunol 2003; 4:1199–1205.PubMedCrossRefGoogle Scholar
  140. 140.
    Demeure CE, Brahimi K, Hacini F et al. Anopheles mosquito bites activate cutaneous mast cells leading to a local inflammatory response and lymph node hyperplasia. J Immunol 2005; 174:3932–3940.PubMedGoogle Scholar
  141. 141.
    Mallen-St Clair J, Pham CT, Villalta SA et al. Mast cell dipeptidyl peptidase I mediates survival from sepsis. J Clin Invest 2004; 113:628–634.Google Scholar
  142. 142.
    Metz M, Maurer M. Innate immunity and allergy in the skin. Curr Opin Immunol 2009; 21:687–693.PubMedCrossRefGoogle Scholar
  143. 143.
    Maurer M, Lopez Kostka S, Siebenhaar F et al. Skin mast cells control T-cell-dependent host defense in Leishmania major infections. FASEB J 2006; 20:2460–2467.PubMedCrossRefGoogle Scholar
  144. 144.
    Shin K, Watts GF, Oettgen HC et al. Mouse mast cell tryptase mMCP-6 is a critical link between adaptive and innate immunity in the chronic phase of Trichinella spiralis infection. J Immunol 2008; 180:4885–4891.PubMedGoogle Scholar
  145. 145.
    Galli SJ, Tsai M. Mast cells in allergy and infection: versatile effector and regulatory cells in innate and acquired immunity. Eur J Immunol 2010; 40:1843–1851.PubMedCrossRefGoogle Scholar
  146. 146.
    Bischoff SC. Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol 2007; 7:93–104.PubMedCrossRefGoogle Scholar
  147. 147.
    Takenaka H, Ushio H, Niyonsaba F et al. Synergistic augmentation of inflammatory cytokine productions from murine mast cells by monomeric IgE and toll-like receptor ligands. Biochem Biophys Res Commun 2010; 391:471–476.PubMedCrossRefGoogle Scholar
  148. 148.
    Qiao H, Andrade MV, Lisboa FA et al. FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 2006; 107:610–618.PubMedCrossRefGoogle Scholar
  149. 149.
    Hart PH, Townley SL, Grimbaldeston MA et al. Mast cells, neuropeptides, histamine and prostaglandins in UV-induced systemic immunosuppression. Methods 2002; 28:79–89.PubMedCrossRefGoogle Scholar
  150. 150.
    Metz M, Lammel V, Gibbs BF et al. Inflammatory murine skin responses to UV-B light are partially dependent on endothelin-1 and mast cells. Am J Pathol 2006; 169:815–822.PubMedCrossRefGoogle Scholar
  151. 151.
    Biggs L et al. Evidence that vitamin D3 promotes mast cell-dependent reduction of chronic UVB-induced skin pathology in mice. J Exp Med 2010; 207:455–463.PubMedCrossRefGoogle Scholar
  152. 152.
    Alard P, Niizeki H, Hanninen L et al. Local ultraviolet B irradiation impairs contact hypersensitivity induction by triggering release of tumor necrosis factor-alpha from mast cells. Involvement of mast cells and Langerhans cells in susceptibility to ultraviolet B. J Invest Dermatol 1999; 113:983–990.PubMedCrossRefGoogle Scholar
  153. 153.
    Secor VH, Secor WE, Gutekunst CA et al. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J Exp Med 2000; 191:813–822.PubMedCrossRefGoogle Scholar
  154. 154.
    Robbie-Ryan M, Tanzola MB, Secor VH et al. Cutting edge: both activating and inhibitory Fc receptors expressed on mast cells regulate experimental allergic encephalomyelitis disease severity. J Immunol 2003; 170:1630–1634.PubMedGoogle Scholar
  155. 155.
    Gregory GD, Raju SS, Winandy S et al. Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE. J Clin Invest 2006; 116:1327–1336.PubMedCrossRefGoogle Scholar
  156. 156.
    Sayed BA, Christy AL, Walker ME et al. Meningeal mast cells affect early T-cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment? J Immunol 2010; 184:6891–6900.PubMedCrossRefGoogle Scholar
  157. 157.
    Williams CM, Galli SJ. The diverse potential effector and immunoregulatory roles of mast cells in allergic disease. J Allergy Clin Immunol 2000; 105:847–859.PubMedCrossRefGoogle Scholar
  158. 158.
    Yu M, Tsai M, Tam SY et al. Mast cells can promote the development of multiple features of chronic asthma in mice. J Clin Invest 2006; 116:1633–1641.PubMedCrossRefGoogle Scholar
  159. 159.
    Williams CM, Galli SJ. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J Exp Med 2000; 192:455–462.PubMedCrossRefGoogle Scholar
  160. 160.
    Taube C, Wei X, Swasey CH et al. Mast cells, FcepsilonRI and IL-13 are required for development of airway hyperresponsiveness after aerosolized allergen exposure in the absence of adjuvant. J Immunol 2004; 172:6398–6406.PubMedGoogle Scholar
  161. 161.
    Nakae S, Ho LH, Yu M et al. Mast cell-derived TNF contributes to airway hyperreactivity, inflammation and TH2 cytokine production in an asthma model in mice. J Allergy Clin Immunol 2007; 120:48–55.PubMedCrossRefGoogle Scholar
  162. 162.
    Kim YS, Ko HM, Kang NI et al. Mast cells play a key role in the development of late airway hyperresponsiveness through TNF-alpha in a murine model of asthma. Eur J Immunol 2007;37:1107–1115.PubMedCrossRefGoogle Scholar
  163. 163.
    Reuter S, Heinz A, Sieren M et al. Mast cell-derived tumour necrosis factor is essential for allergic airway disease. Eur Respir J 2008; 31:773–782.PubMedCrossRefGoogle Scholar
  164. 164.
    Goodarzi K, Goodarzi M, Tager AM et al. Leukotriene B4 and BLT1 control cytotoxic effector T-cell recruitment to inflamed tissues. Nat Immunol 2003; 4:965–973.PubMedCrossRefGoogle Scholar
  165. 165.
    Tager AM, Bromley SK, Medoff BD et al. Leukotriene B4 receptor BLT1 mediates early effector T-cell recruitment. Nat Immunol 2003; 4:982–990.PubMedCrossRefGoogle Scholar
  166. 166.
    Ott VL, Cambier JC, Kappler J et al. Mast cell-dependent migration of effector CD8+ T-cells through production of leukotriene B4. Nat Immunol 2003; 4:974–981.PubMedCrossRefGoogle Scholar
  167. 167.
    Nakae S, Suto H, Berry GJ et al. Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice. Blood 2007; 109:3640–3648.PubMedCrossRefGoogle Scholar
  168. 168.
    Waern I, Jonasson S, Hjoberg J et al. Mouse mast cell protease 4 is the major chymase in murine airways and has a protective role in allergic airway inflammation. J Immunol 2009; 183:6369–6376.PubMedCrossRefGoogle Scholar
  169. 169.
    Kakurai M, Monteforte R, Suto H et al. Mast cell-derived tumor necrosis factor can promote nerve fiber elongation in the skin during contact hypersensitivity in mice. Am J Pathol 2006; 169:1713–1721.PubMedCrossRefGoogle Scholar
  170. 170.
    Norman MU, Hwang J, Hulliger S et al. Mast cells regulate the magnitude and the cytokine microenvironment of the contact hypersensitivity response. Am J Pathol 2008; 172:1638–1649.PubMedCrossRefGoogle Scholar
  171. 171.
    Lee DM, Friend DS, Gurish MF et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002; 297:1689–1692.PubMedCrossRefGoogle Scholar
  172. 172.
    Nigrovic PA, Binstadt BA, Monach PA et al. Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. Proc Natl Acad Sci USA 2007; 104:2325–2330.PubMedCrossRefGoogle Scholar
  173. 173.
    Chen R, Ning G, Zhao ML et al. Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest 2001; 108:1151–1158.PubMedGoogle Scholar
  174. 174.
    Scandiuzzi L, Beghdadi W, Daugas E et al. Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis. J Immunol 2010; 185:624–633.PubMedCrossRefGoogle Scholar
  175. 175.
    Depinay N, Hacini F, Beghdadi W et al. Mast cell-dependent down-regulation of antigen-specific immune responses by mosquito bites. J Immunol 2006; 176:4141–4146.PubMedGoogle Scholar
  176. 176.
    Limon-Flores AY, Chacon-Salinas R, Ramos G et al. Mast cells mediate the immune suppression induced by dermal exposure to JP-8 jet fuel. Toxicol Sci 2009; 112:144–152.PubMedCrossRefGoogle Scholar
  177. 177.
    Beissert S, Schwarz A, Schwarz T. Regulatory T-cells. J Invest Dermatol 2006; 126:15–24.PubMedCrossRefGoogle Scholar
  178. 178.
    O’Garra A, Vieira P. TH1 cells control themselves by producing interleukin-10. Nat Rev Immunol 2007; 7:425–428.PubMedCrossRefGoogle Scholar
  179. 179.
    Frossi B, Gri G, Tripodo C et al. Exploring a regulatory role for mast cells: ‘MCregs’? Trends Immunol 2010; 31:97–102.PubMedCrossRefGoogle Scholar
  180. 180.
    Hershko AY, Rivera J. Mast cell and T-cell communication; amplification and control of adaptive immunity. Immunol Lett 2010; 128:98–104.PubMedCrossRefGoogle Scholar
  181. 181.
    Boerma M, Fiser WP, Hoyt G et al. Influence of mast cells on outcome after heterotopic cardiac transplantation in rats. Transpl Int 2007; 20:256–265.PubMedCrossRefGoogle Scholar
  182. 182.
    Itoh S, Nakae S, Velotta JB et al. The role of recipient mast cells in acute and chronic cardiac allograft rejection in C57BL/6-KitW-sh/W-sh mice. J Heart Lung Transplant 2010; 29:401–409.PubMedCrossRefGoogle Scholar
  183. 183.
    de Vries VC, Wasiuk A, Bennett KA et al. Mast cell degranulation breaks peripheral tolerance. Am J Transplant 2009; 9:2270–2280.PubMedCrossRefGoogle Scholar
  184. 184.
    Piconese S, Gri G, Tripodo C et al. Mast cells counteractregulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood 2009; 114:2639–2648.PubMedGoogle Scholar
  185. 185.
    Gri G, Piconese S, Frossi B et al. CD4+CD25+ regulatory T-cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 2008; 29:771–781.PubMedCrossRefGoogle Scholar
  186. 186.
    Askenase PW, Van Loveren H, Kraeuter-Kops S et al. Defective elicitation of delayed-type hypersensitivity in W/Wv and Sl/Sld mast cell-deficient mice. J Immunol 1983; 131:2687–2694.PubMedGoogle Scholar
  187. 187.
    Biedermann T, Kneilling M, Mailhammer R et al. Mast cells control neutrophil recruitment during T-cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J Exp Med 2000; 192:1441–1452.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2011

Authors and Affiliations

  • Mindy Tsai
    • 1
  • Michele Grimbaldeston
    • 3
  • Stephen J. Galli
    • 1
    • 2
  1. 1.Department of PathologyStanford University School of MedicineStanfordUSA
  2. 2.Department of Microbiology and ImmunologyStanford University School of MedicineStanfordUSA
  3. 3.Division of Human Immunology, Centre for Cancer Biology, and Schools of Molecular and Biomedical Sciences or MedicineUniversity of AdelaideAdelaideAustralia

Personalised recommendations