Cancer Immunology, Immunotherapy

, Volume 60, Issue 8, pp 1061–1074

Cooperativity of adaptive and innate immunity: implications for cancer therapy



The dichotomy of immunology into innate and adaptive immunity has created conceptual barriers in appreciating the intrinsic two-way interaction between immune cells. An emerging body of evidence in various models of immune rejection, including cancer, indicates an indispensable regulation of innate effector functions by adaptive immune cells. This bidirectional cooperativity in innate and adaptive immune functions has broad implications for immune responses in general and for regulating the tumor-associated inflammation that overrides the protective antitumor immunity. Mechanistic understanding of this two-way immune cross-talk could provide insights into novel strategies for designing better immunotherapy approaches against cancer and other diseases that normally defy immune control.


Innate immunity Adaptive T cells Natural killer cells Effector function Immune regulation Cancer immunotherapy 


  1. 1.
    Pancer Z, Cooper MD (2006) The evolution of adaptive immunity. Annual Rev Immunol 24:497–518. doi:10.1146/annurev.immunol.24.021605.090542 CrossRefGoogle Scholar
  2. 2.
    Rolff J (2007) Why did the acquired immune system of vertebrates evolve? Dev Comp Immunol 31(5):476–482. doi:10.1016/j.dci.2006.08.009 PubMedCrossRefGoogle Scholar
  3. 3.
    Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327(5963):291–295. doi:10.1126/science.1183021 PubMedCrossRefGoogle Scholar
  4. 4.
    Little TJ, Hultmark D, Read AF (2005) Invertebrate immunity and the limits of mechanistic immunology. Nat Immunol 6(7):651–654. doi:10.1038/ni1219 PubMedCrossRefGoogle Scholar
  5. 5.
    Boman HG, Nilsson I, Rasmuson B (1972) Inducible antibacterial defence system in Drosophila. Nature 237(5352):232–235PubMedCrossRefGoogle Scholar
  6. 6.
    Pham LN, Dionne MS, Shirasu-Hiza M, Schneider DS (2007) A specific primed immune response in Drosophila is dependent on phagocytes. PLoS Pathog 3 (3):e26. doi:10.1371/journal.ppat.0030026
  7. 7.
    Moret Y, Siva-Jothy MT (2003) Adaptive innate immunity? Responsive-mode prophylaxis in the mealworm beetle, Tenebrio molitor. Proc Biol Sci 270(1532):2475–2480. doi:10.1098/rspb.2003.2511 PubMedCrossRefGoogle Scholar
  8. 8.
    Rodrigues J, Brayner FA, Alves LC, Dixit R, Barillas-Mury C (2010) Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes. Science 329(5997):1353–1355. doi:10.1126/science.1190689 PubMedCrossRefGoogle Scholar
  9. 9.
    Haine ER, Moret Y, Siva-Jothy MT, Rolff J (2008) Antimicrobial defense and persistent infection in insects. Science 322(5905):1257–1259. doi:10.1126/science.1165265 PubMedCrossRefGoogle Scholar
  10. 10.
    Rahman MM, Roberts HL, Sarjan M, Asgari S, Schmidt O (2004) Induction and transmission of Bacillus thuringiensis tolerance in the flour moth Ephestia kuehniella. Proc Natl Acad Sci USA 101(9):2696–2699. doi:10.1073/pnas.0306669101 PubMedCrossRefGoogle Scholar
  11. 11.
    Little TJ, O’Connor B, Colegrave N, Watt K, Read AF (2003) Maternal transfer of strain-specific immunity in an invertebrate. Curr Biol 13(6):489–492. doi:S0960982203001635 PubMedCrossRefGoogle Scholar
  12. 12.
    Hildemann WH, Johnson IS, Jokiel PL (1979) Immunocompetence in the lowest metazoan phylum: transplantation immunity in sponges. Science 204(4391):420–422PubMedCrossRefGoogle Scholar
  13. 13.
    Kurtz J (2005) Specific memory within innate immune systems. Trends Immunol 26(4):186–192. doi:10.1016/ PubMedCrossRefGoogle Scholar
  14. 14.
    Little TJ, Kraaijeveld AR (2004) Ecological and evolutionary implications of immunological priming in invertebrates. Trends Ecol Evol 19(2):58–60. doi:10.1016/j.tree.2003.11.011 PubMedCrossRefGoogle Scholar
  15. 15.
    Ghosh J, Buckley KM, Nair SV, Raftos DA, Miller C, Majeske AJ, Hibino T, Rast JP, Roth M, Smith LC (2010) Sp185/333: a novel family of genes and proteins involved in the purple sea urchin immune response. Dev Comp Immunol 34(3):235–245. doi:10.1016/j.dci.2009.10.008 PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang SM, Adema CM, Kepler TB, Loker ES (2004) Diversification of Ig superfamily genes in an invertebrate. Science 305(5681):251–254. doi:10.1126/science.1088069 PubMedCrossRefGoogle Scholar
  17. 17.
    Pancer Z, Amemiya CT, Ehrhardt GR, Ceitlin J, Gartland GL, Cooper MD (2004) Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430(6996):174–180. doi:10.1038/nature02740 PubMedCrossRefGoogle Scholar
  18. 18.
    Boehm T (2011) Design principles of adaptive immune systems. Nat Rev Immunol 11(5):307–317. doi:10.1038/nri2944 PubMedCrossRefGoogle Scholar
  19. 19.
    Park JK, Kim KH, Kang S, Kim W, Eom KS, Littlewood DT (2007) A common origin of complex life cycles in parasitic flatworms: evidence from the complete mitochondrial genome of Microcotyle sebastis (Monogenea: Platyhelminthes). BMC Evol Biol 7:11. doi:10.1186/1471-2148-7-11 PubMedCrossRefGoogle Scholar
  20. 20.
    Cheroutre H (2004) Starting at the beginning: new perspectives on the biology of mucosal T cells. Annu Rev Immunol 22:217–246. doi:10.1146/annurev.immunol.22.012703.104522 PubMedCrossRefGoogle Scholar
  21. 21.
    Lee YK, Mazmanian SK (2010) Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330(6012):1768–1773. doi:10.1126/science.1195568 PubMedCrossRefGoogle Scholar
  22. 22.
    Guo P, Hirano M, Herrin BR, Li J, Yu C, Sadlonova A, Cooper MD (2009) Dual nature of the adaptive immune system in lampreys. Nature 459(7248):796–801. doi:10.1038/nature08068 PubMedCrossRefGoogle Scholar
  23. 23.
    Litman GW, Rast JP, Fugmann SD (2010) The origins of vertebrate adaptive immunity. Nat Rev Immunol 10(8):543–553PubMedCrossRefGoogle Scholar
  24. 24.
    McLysaght A, Hokamp K, Wolfe KH (2002) Extensive genomic duplication during early chordate evolution. Nat Genet 31(2):200–204. doi:10.1038/ng884 PubMedCrossRefGoogle Scholar
  25. 25.
    Gillooly JF, Allen AP, West GB, Brown JH (2005) The rate of DNA evolution: effects of body size and temperature on the molecular clock. Proc Natl Acad Sci USA 102(1):140–145. doi:10.1073/pnas.0407735101 PubMedCrossRefGoogle Scholar
  26. 26.
    Rodin SN, Parkhomchuk DV, Riggs AD (2005) Epigenetic changes and repositioning determine the evolutionary fate of duplicated genes. Biochemistry (Mosc) 70(5):559–567. doi:BCM70050680 Google Scholar
  27. 27.
    Chan TA, Glockner S, Yi JM, Chen W, Van Neste L, Cope L, Herman JG, Velculescu V, Schuebel KE, Ahuja N, Baylin SB (2008) Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 5(5):e114. doi:10.1371/journal.pmed.0050114
  28. 28.
    Capasso LL (2005) Antiquity of cancer. Int J Cancer 113(1):2–13. doi:10.1002/ijc.20610 PubMedCrossRefGoogle Scholar
  29. 29.
    Ogasawara K, Lanier LL (2005) NKG2D in NK and T cell-mediated immunity. J Clin Immunol 25(6):534–540. doi:10.1007/s10875-005-8786-4 PubMedCrossRefGoogle Scholar
  30. 30.
    Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3(10):781–790. doi:10.1038/nri1199 PubMedCrossRefGoogle Scholar
  31. 31.
    Kelley J, Walter L, Trowsdale J (2005) Comparative genomics of natural killer cell receptor gene clusters. PLoS Genet 1(2):129–139. doi:10.1371/journal.pgen.0010027 PubMedGoogle Scholar
  32. 32.
    Knight SC, Askonas BA, Macatonia SE (1997) Dendritic cells as targets for cytotoxic T lymphocytes. Adv Exp Med Biol 417:389–394PubMedGoogle Scholar
  33. 33.
    Ludewig B, Bonilla WV, Dumrese T, Odermatt B, Zinkernagel RM, Hengartner H (2001) Perforin-independent regulation of dendritic cell homeostasis by CD8(+) T cells in vivo: implications for adaptive immunotherapy. Eur J Immunol 31(6):1772–1779. doi:10.1002/1521-4141(200106)31:6<1772:AID-IMMU1772>3.0.CO;2-8 PubMedCrossRefGoogle Scholar
  34. 34.
    Hermans IF, Ritchie DS, Yang J, Roberts JM, Ronchese F (2000) CD8+ T cell-dependent elimination of dendritic cells in vivo limits the induction of antitumor immunity. J Immunol 164(6):3095–3101. doi:ji_v164n6p3095 PubMedGoogle Scholar
  35. 35.
    Manickasingham S, Reis e Sousa C (2000) Microbial and T cell-derived stimuli regulate antigen presentation by dendritic cells in vivo. J Immunol 165(9):5027–5034PubMedGoogle Scholar
  36. 36.
    Bai L, Beckhove P, Feuerer M, Umansky V, Choi C, Solomayer FS, Diel IJ, Schirrmacher V (2003) Cognate interactions between memory T cells and tumor antigen-presenting dendritic cells from bone marrow of breast cancer patients: bidirectional cell stimulation, survival and antitumor activity in vivo. Int J Cancer 103(1):73–83. doi:10.1002/ijc.10781 PubMedCrossRefGoogle Scholar
  37. 37.
    Wong KL, Lew FC, MacAry PA, Kemeny DM (2008) CD40L-expressing CD8 T cells prime CD8alpha(+) DC for IL-12p70 production. Eur J Immunol 38(8):2251–2262. doi:10.1002/eji.200838199 PubMedCrossRefGoogle Scholar
  38. 38.
    Chong SZ, Wong KL, Lin G, Yang CM, Wong SC, Angeli V, Macary PA, Kemeny DM (2011) Human CD8 T-cells drive Th1 responses through the differentiation of TNF/iNOS-producing dendritic cells. Eur J Immunol 41(6):1639–1651. doi:10.1002/eji.201041022 Google Scholar
  39. 39.
    O’Shea JJ, Murray PJ (2008) Cytokine signaling modules in inflammatory responses. Immunity 28(4):477–487. doi:10.1016/j.immuni.2008.03.002 PubMedCrossRefGoogle Scholar
  40. 40.
    Haan C, Kreis S, Margue C, Behrmann I (2006) Jaks and cytokine receptors: an intimate relationship. Biochem Pharmacol 72(11):1538–1546. doi:10.1016/j.bcp.2006.04.013 PubMedCrossRefGoogle Scholar
  41. 41.
    Schroder K, Sweet MJ, Hume DA (2006) Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology 211(6–8):511–524. doi:10.1016/j.imbio.2006.05.007 PubMedCrossRefGoogle Scholar
  42. 42.
    Rosner D, Stoneman V, Littlewood T, McCarthy N, Figg N, Wang Y, Tellides G, Bennett M (2006) Interferon-gamma induces Fas trafficking and sensitization to apoptosis in vascular smooth muscle cells via a PI3K- and Akt-dependent mechanism. Am J Pathol 168(6):2054–2063. doi:168/6/2054 PubMedGoogle Scholar
  43. 43.
    Shanker A, Brooks AD, Jacobsen KM, Wine JW, Wiltrout RH, Yagita H, Sayers TJ (2009) Antigen presented by tumors in vivo determines the nature of CD8+ T-cell cytotoxicity. Cancer Res 69(16):6615–6623. doi:10.1158/0008-5472.CAN-09-0685 PubMedCrossRefGoogle Scholar
  44. 44.
    Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B (2004) Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21(3):357–366. doi:10.1016/j.immuni.2004.06.020 PubMedCrossRefGoogle Scholar
  45. 45.
    Bezbradica JS, Medzhitov R (2009) Integration of cytokine and heterologous receptor signaling pathways. Nature Immunol 10(4):333–339. doi:10.1038/ni.1713 CrossRefGoogle Scholar
  46. 46.
    Budagian V, Bulanova E, Paus R, Bulfone-Paus S (2006) IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev 17(4):259–280. doi:10.1016/j.cytogfr.2006.05.001 PubMedCrossRefGoogle Scholar
  47. 47.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450(7171):903–907PubMedCrossRefGoogle Scholar
  48. 48.
    Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W, Kim J, Simpson AJ, Old LJ, Cui Z (2006) Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci USA 103(20):7753–7758PubMedCrossRefGoogle Scholar
  49. 49.
    Hicks AM, Willingham MC, Du W, Pang CS, Old LJ, Cui Z (2006) Effector mechanisms of the anti-cancer immune responses of macrophages in SR/CR mice. Cancer Immun 6:11PubMedGoogle Scholar
  50. 50.
    Yu YA, Galanis C, Woo Y, Chen N, Zhang Q, Fong Y, Szalay AA (2009) Regression of human pancreatic tumor xenografts in mice after a single systemic injection of recombinant vaccinia virus GLV-1h68. Mol Cancer Ther 8(1):141–151PubMedCrossRefGoogle Scholar
  51. 51.
    Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H, Monsurro V, Buller RM, Stroncek DF, Wang E, Szalay AA, Marincola FM (2009) Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy. BMC Genomics 10:301. doi:10.1186/1471-2164-10-301 PubMedCrossRefGoogle Scholar
  52. 52.
    Shanker A, Auphan-Anezin N, Chomez P, Giraudo L, Van den Eynde B, Schmitt-Verhulst AM (2004) Thymocyte-intrinsic genetic factors influence CD8 T cell lineage commitment and affect selection of a tumor-reactive TCR. J Immunol 172(8):5069–5077PubMedGoogle Scholar
  53. 53.
    Shanker A, Verdeil G, Buferne M, Inderberg-Suso EM, Puthier D, Joly F, Nguyen C, Leserman L, Auphan-Anezin N, Schmitt-Verhulst AM (2007) CD8 T cell help for innate antitumor immunity. J Immunol 179(10):6651–6662PubMedGoogle Scholar
  54. 54.
    Shanker A, Schmitt-Verhulst AM, Inderberg-Suso EM (2004) Monoclonal CD8 T lymphocytes recognizing a self tumor associated antigen provide resistance to tumor development in vivo in synergy with NK cells. Faseb J 18(4):A83–A83Google Scholar
  55. 55.
    Shanker A, Buferne M, Schmitt-Verhulst A-M (2009) Cooperative action of CD8 T lymphocytes and natural killer cells controls tumour growth under conditions of restricted T-cell receptor diversity. Immunology 129:41–54. doi:10.1111/j.1365-2567.2009.03150.x CrossRefGoogle Scholar
  56. 56.
    Kabingu E, Vaughan L, Owczarczak B, Ramsey KD, Gollnick SO (2007) CD8+ T cell-mediated control of distant tumours following local photodynamic therapy is independent of CD4+ T cells and dependent on natural killer cells. Br J Cancer 96(12):1839–1848. doi:10.1038/sj.bjc.6603792 PubMedCrossRefGoogle Scholar
  57. 57.
    Perez-Diez A, Joncker NT, Choi K, Chan WF, Anderson CC, Lantz O, Matzinger P (2007) CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood 109(12):5346–5354. doi:10.1182/blood-2006-10-051318 PubMedCrossRefGoogle Scholar
  58. 58.
    Arina A, Murillo O, Hervas-Stubbs S, Azpilikueta A, Dubrot J, Tirapu I, Huarte E, Alfaro C, Perez-Gracia JL, Gonzalez-Aseguinolaza G, Sarobe P, Lasarte JJ, Jamieson A, Prieto J, Raulet DH, Melero I (2007) The combined actions of NK and T lymphocytes are necessary to reject an EGFP+ mesenchymal tumor through mechanisms dependent on NKG2D and IFN gamma. Int J Cancer 121(6):1282–1295. doi:10.1002/ijc.22795 PubMedCrossRefGoogle Scholar
  59. 59.
    Soudja SM, Wehbe M, Mas A, Chasson L, de Tenbossche CP, Huijbers I, Van den Eynde B, Schmitt-Verhulst A-M (2010) Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice. Cancer Res 70(9):3515–3525. doi:10.1158/0008-5472.can-09-4354 PubMedCrossRefGoogle Scholar
  60. 60.
    Dethlefsen L, McFall-Ngai M, Relman DA (2007) An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 449(7164):811–818. doi:10.1038/nature06245 PubMedCrossRefGoogle Scholar
  61. 61.
    Greer JB, O’Keefe SJ (2011) Microbial induction of immunity, inflammation, and cancer. Front Physiol 1:168. doi:10.3389/fphys.2010.00168 PubMedGoogle Scholar
  62. 62.
    Saleh M, Trinchieri G (2011) Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol 11(1):9–20. doi:10.1038/nri2891 PubMedGoogle Scholar
  63. 63.
    Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA 105(52):20858–20863. doi:10.1073/pnas.0808723105 PubMedCrossRefGoogle Scholar
  64. 64.
    Macpherson AJ, Uhr T (2004) Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303(5664):1662–1665PubMedCrossRefGoogle Scholar
  65. 65.
    Slack E, Hapfelmeier S, Stecher B, Velykoredko Y, Stoel M, Lawson MA, Geuking MB, Beutler B, Tedder TF, Hardt WD, Bercik P, Verdu EF, McCoy KD, Macpherson AJ (2009) Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325(5940):617–620. doi:10.1126/science.1172747 PubMedCrossRefGoogle Scholar
  66. 66.
    Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, Tang M, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T, Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Marodi L, Garty BZ, Chapel H, Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A, Casanova JL (2007) Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med 204(10):2407–2422. doi:10.1084/jem.20070628 PubMedCrossRefGoogle Scholar
  67. 67.
    Ku CL, Picard C, Erdos M, Jeurissen A, Bustamante J, Puel A, von Bernuth H, Filipe-Santos O, Chang HH, Lawrence T, Raes M, Marodi L, Bossuyt X, Casanova JL (2007) IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet 44(1):16–23. doi:10.1136/jmg.2006.044446 PubMedGoogle Scholar
  68. 68.
    Lertmemongkolchai G, Cai G, Hunter CA, Bancroft GJ (2001) Bystander activation of CD8 + T cells contributes to the rapid production of IFN-gamma in response to bacterial pathogens. J Immunol 166(2):1097–1105PubMedGoogle Scholar
  69. 69.
    Hajishengallis G, Lambris JD (2011) Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol 11(3):187–200. doi:10.1038/nri2918 PubMedCrossRefGoogle Scholar
  70. 70.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. doi:10.1016/j.cell.2010.01.025 PubMedCrossRefGoogle Scholar
  71. 71.
    Levy O (2007) Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 7(5):379–390. doi:10.1038/nri2075 PubMedCrossRefGoogle Scholar
  72. 72.
    Zhao J, Liu J, Feng Z, Hu S, Liu Y, Sheng X, Li S, Wang X, Long C (2008) Clinical outcomes and experience of 20 pediatric patients treated with extracorporeal membrane oxygenation in Fuwai Hospital. ASAIO J 54(3):302–305. doi:10.1097/MAT.0b013e318172b445 PubMedCrossRefGoogle Scholar
  73. 73.
    Atici A, Satar M, Cetiner S, Yaman A (1997) Serum tumor necrosis factor-alpha in neonatal sepsis. Am J Perinatol 14(7):401–404PubMedCrossRefGoogle Scholar
  74. 74.
    Blackwell CC, Moscovis SM, Gordon AE, Al Madani OM, Hall ST, Gleeson M, Scott RJ, Roberts-Thomson J, Weir DM, Busuttil A (2005) Cytokine responses and sudden infant death syndrome: genetic, developmental, and environmental risk factors. J Leuk Biol 78(6):1242–1254. doi:10.1189/jlb.0505253 CrossRefGoogle Scholar
  75. 75.
    Ozdemir A, Oygur N, Gultekin M, Coskun M, Yegin O (1994) Neonatal tumor necrosis factor, interleukin-1 alpha, interleukin-1 beta, and interleukin-6 response to infection. Am J Perinatol 11(4):282–285PubMedCrossRefGoogle Scholar
  76. 76.
    Vege A, Rognum TO, Aasen AO, Saugstad OD (1998) Are elevated cerebrospinal fluid levels of IL-6 in sudden unexplained deaths, infectious deaths and deaths due to heart/lung disease in infants and children due to hypoxia? Acta Paediatr 87(8):819–824PubMedCrossRefGoogle Scholar
  77. 77.
    Zhang X, Deriaud E, Jiao X, Braun D, Leclerc C, Lo-Man R (2007) Type I interferons protect neonates from acute inflammation through interleukin 10-producing B cells. J Exp Med 204(5):1107–1118. doi:10.1084/jem.20062013 PubMedCrossRefGoogle Scholar
  78. 78.
    Miyara M, Sakaguchi S (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13(3):108–116. doi:10.1016/j.molmed.2007.01.003 PubMedCrossRefGoogle Scholar
  79. 79.
    Heldrup J, Kalm O, Prellner K (1992) Blood T and B lymphocyte subpopulations in healthy infants and children. Acta Paediatr 81(2):125–132PubMedCrossRefGoogle Scholar
  80. 80.
    Kumar A, Jauhari P, Singh U, Singla PN (1994) Quantitation of T cells in venous blood of healthy neonates. Indian J Pediatr 61(6):711–714PubMedCrossRefGoogle Scholar
  81. 81.
    Lund JM, Hsing L, Pham TT, Rudensky AY (2008) Coordination of early protective immunity to viral infection by regulatory T cells. Science 320(5880):1220–1224. doi:10.1126/science.1155209 PubMedCrossRefGoogle Scholar
  82. 82.
    Kim KD, Zhao J, Auh S, Yang X, Du P, Tang H, Fu YX (2007) Adaptive immune cells temper initial innate responses. Nat Med 13(10):1248–1252. doi:10.1038/nm1633 PubMedGoogle Scholar
  83. 83.
    Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426PubMedCrossRefGoogle Scholar
  84. 84.
    Guarda G, Dostert C, Staehli F, Cabalzar K, Castillo R, Tardivel A, Schneider P, Tschopp J (2009) T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 460(7252):269–273. doi:10.1038/nature08100 PubMedCrossRefGoogle Scholar
  85. 85.
    Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10(4):348–355. doi:10.1038/ni.1714 PubMedCrossRefGoogle Scholar
  86. 86.
    Sun K, Metzger DW (2008) Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat Med 14(5):558–564. doi:10.1038/nm1765 PubMedCrossRefGoogle Scholar
  87. 87.
    Horowitz A, Behrens RH, Okell L, Fooks AR, Riley EM (2010) NK cells as effectors of acquired immune responses: effector CD4+ T cell-dependent activation of NK cells following vaccination. J Immunol 185(5):2808–2818. doi:10.4049/jimmunol.1000844 Google Scholar
  88. 88.
    Horowitz A, Newman KC, Evans JH, Korbel DS, Davis DM, Riley EM (2010) Cross-talk between T cells and NK cells generates rapid effector responses to Plasmodium falciparum-infected erythrocytes. J Immunol 184(11):6043-6052. doi:10.4049/jimmunol.1000106 Google Scholar
  89. 89.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867. doi:10.1038/nature05485 PubMedCrossRefGoogle Scholar
  90. 90.
    Wu H, Ghosh S, Perrard XD, Feng L, Garcia GE, Perrard JL, Sweeney JF, Peterson LE, Chan L, Smith CW, Ballantyne CM (2007) T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115(8):1029–1038. doi:10.1161/CIRCULATIONAHA.106.638379 PubMedCrossRefGoogle Scholar
  91. 91.
    Rausch ME, Weisberg S, Vardhana P, Tortoriello DV (2008) Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 32(3):451–463. doi:10.1038/sj.ijo.0803744 CrossRefGoogle Scholar
  92. 92.
    Duffaut C, Galitzky J, Lafontan M, Bouloumie A (2009) Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem Biophys Res Commun 384(4):482–485. doi:10.1016/j.bbrc.2009.05.002 PubMedCrossRefGoogle Scholar
  93. 93.
    Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15(8):914–920. doi:10.1038/nm.1964 PubMedCrossRefGoogle Scholar
  94. 94.
    Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15(8):921–929. doi:10.1038/nm.2001 PubMedCrossRefGoogle Scholar
  95. 95.
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15(8):930–939. doi:10.1038/nm.2002 PubMedCrossRefGoogle Scholar
  96. 96.
    Gurlo T, von Grafenstein H (2003) Antigen-independent cross-talk between macrophages and CD8+ T cells facilitates their cooperation during target destruction. Int Immunol 15(9):1063–1071PubMedCrossRefGoogle Scholar
  97. 97.
    Andersson J, Libby P, Hansson GK (2010) Adaptive immunity and atherosclerosis. Clin Immunol 134:33–46. doi:10.1016/j.clim.2009.07.002 PubMedCrossRefGoogle Scholar
  98. 98.
    Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow ME, Fazio S, Wiest MM, Watkins SM, Linton MF, Hotamisligil GS (2009) Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med 15(12):1383–1391. doi:10.1038/nm.2067 PubMedCrossRefGoogle Scholar
  99. 99.
    Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S, Korets L, Lam J, Tawfik D, DeNardo DG, Naldini L, de Visser KE, De Palma M, Coussens LM (2010) FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17(2):121–134. doi:10.1016/j.ccr.2009.12.019 PubMedCrossRefGoogle Scholar
  100. 100.
    Wong SC, Puaux AL, Chittezhath M, Shalova I, Kajiji TS, Wang X, Abastado JP, Lam KP, Biswas SK (2010) Macrophage polarization to a unique phenotype driven by B cells. Eur J Immunol 40(8):2296–2307. doi:10.1002/eji.200940288 PubMedCrossRefGoogle Scholar
  101. 101.
    DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM (2009) CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16(2):91–102. doi:10.1016/j.ccr.2009.06.018 PubMedCrossRefGoogle Scholar
  102. 102.
    Cittera E, Leidi M, Buracchi C, Pasqualini F, Sozzani S, Vecchi A, Waterfield JD, Introna M, Golay J (2007) The CCL3 family of chemokines and innate immunity cooperate in vivo in the eradication of an established lymphoma xenograft by rituximab. J Immunol 178(10):6616–6623. doi:178/10/6616 PubMedGoogle Scholar
  103. 103.
    Maeno T, Houghton AM, Quintero PA, Grumelli S, Owen CA, Shapiro SD (2007) CD8+ T Cells are required for inflammation and destruction in cigarette smoke-induced emphysema in mice. J Immunol 178(12):8090–8096. doi:178/12/8090 PubMedGoogle Scholar
  104. 104.
    Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357–1361PubMedCrossRefGoogle Scholar
  105. 105.
    Narni-Mancinelli E, Campisi L, Bassand D, Cazareth J, Gounon P, Glaichenhaus N, Lauvau G (2007) Memory CD8+ T cells mediate antibacterial immunity via CCL3 activation of TNF/ROI+ phagocytes. J Exp Med 204(9):2075–2087. doi:10.1084/jem.20070204 PubMedCrossRefGoogle Scholar
  106. 106.
    McKinstry KK, Strutt TM, Swain SL (2010) The potential of CD4 T-cell memory. Immunology 130(1):1–9. doi:10.1111/j.1365-2567.2010.03259.x PubMedCrossRefGoogle Scholar
  107. 107.
    O’Leary JG, Goodarzi M, Drayton DL, von Andrian UH (2006) T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 7(5):507–516. doi:10.1038/ni1332 PubMedCrossRefGoogle Scholar
  108. 108.
    Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457(7229):557–561. doi:10.1038/nature07665 PubMedCrossRefGoogle Scholar
  109. 109.
    Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, Voigt V, Fleming P, Tabarias H, Hill GR, van der Most RG, Scalzo AA, Smyth MJ, Degli-Esposti MA (2010) Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J Exp Med 207(6):1333–1343. doi:10.1084/jem.20091193 PubMedCrossRefGoogle Scholar
  110. 110.
    Foster SL, Medzhitov R (2009) Gene-specific control of the TLR-induced inflammatory response. Clin Immunol 130(1):7–15. doi:10.1016/j.clim.2008.08.015 PubMedCrossRefGoogle Scholar
  111. 111.
    Foster SL, Hargreaves DC, Medzhitov R (2007) Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447(7147):972–978. doi:10.1038/nature05836 Google Scholar
  112. 112.
    Pham LN, Dionne MS, Shirasu-Hiza M, Schneider DS (2007) A specific primed immune response in Drosophila is dependent on phagocytes. Plos Pathogens 3(3). doi:10.1371/journal.ppat.0030026
  113. 113.
    Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TKA, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie ANJ (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464(7293):1367–1370PubMedCrossRefGoogle Scholar
  114. 114.
    Saenz SA, Siracusa MC, Perrigoue JG, Spencer SP, Urban JF Jr, Tocker JE, Budelsky AL, Kleinschek MA, Kastelein RA, Kambayashi T, Bhandoola A, Artis D (2010) IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464(7293):1362–1366PubMedCrossRefGoogle Scholar
  115. 115.
    Lowy DR, Schiller JT (2006) Prophylactic human papillomavirus vaccines. J Clin Invest 116(5):1167–1173. doi:10.1172/JCI28607 PubMedCrossRefGoogle Scholar
  116. 116.
    Lo-Man R (2011) Regulatory B cells control dendritic cell functions. Immunotherapy 3(4 Suppl):19–20. doi:10.2217/imt.11.34 PubMedCrossRefGoogle Scholar
  117. 117.
    Wang E, Worschech A, Marincola FM (2008) The immunologic constant of rejection. Trends Immunol 29(6):256–262. doi:10.1016/ PubMedCrossRefGoogle Scholar
  118. 118.
    Ascierto ML, Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang E, Ramakrishnan V, Wang XY, Bear HD, Marincola FM, Manjili MH (2011) A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat. doi:10.1007/s10549-011-1470-x
  119. 119.
    Kim SH, Han SY, Azam T, Yoon DY, Dinarello CA (2005) Interleukin-32: a cytokine and inducer of TNFalpha. Immunity 22(1):131–142. doi:10.1016/j.immuni.2004.12.003 PubMedGoogle Scholar
  120. 120.
    Netea MG, Azam T, Ferwerda G, Girardin SE, Walsh M, Park JS, Abraham E, Kim JM, Yoon DY, Dinarello CA, Kim SH (2005) IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism. Proc Natl Acad Sci USA 102(45):16309–16314. doi:10.1073/pnas.0508237102 PubMedCrossRefGoogle Scholar
  121. 121.
    Wang E, Panelli MC, Zavaglia K, Mandruzzato S, Hu N, Taylor PR, Seliger B, Zanovello P, Freedman RS, Marincola FM (2004) Melanoma-restricted genes. J Transl Med 2 (1):34. doi:10.1186/1479-5876-2-34 Google Scholar
  122. 122.
    Monsurro V, Wang E, Yamano Y, Migueles SA, Panelli MC, Smith K, Nagorsen D, Connors M, Jacobson S, Marincola FM (2004) Quiescent phenotype of tumor-specific CD8+ T cells following immunization. Blood 104(7):1970–1978. doi:10.1182/blood-2004-02-0525 PubMedCrossRefGoogle Scholar
  123. 123.
    Critchley-Thorne RJ, Simons DL, Yan N, Miyahira AK, Dirbas FM, Johnson DL, Swetter SM, Carlson RW, Fisher GA, Koong A, Holmes S, Lee PP (2009) Impaired interferon signaling is a common immune defect in human cancer. Proc Natl Acad Sci USA 106(22):9010–9015. doi:10.1073/pnas.0901329106 PubMedCrossRefGoogle Scholar
  124. 124.
    Palucka K, Ueno H, Banchereau J (2011) Recent developments in cancer vaccines. J Immunol 186(3):1325–1331. doi:10.4049/jimmunol.0902539 PubMedCrossRefGoogle Scholar
  125. 125.
    Slezak SL, Worschech A, Wang E, Stroncek DF, Marincola FM (2010) Analysis of vaccine-induced T cells in humans with cancer. Adv Exp Med Biol 684:178–188PubMedCrossRefGoogle Scholar
  126. 126.
    Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, Devera ME, Liang X, Tor M, Billiar T (2007) The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev 220:60–81. doi:10.1111/j.1600-065X.2007.00579.x PubMedCrossRefGoogle Scholar
  127. 127.
    Yang D, de la Rosa G, Tewary P, Oppenheim JJ (2009) Alarmins link neutrophils and dendritic cells. Trends Immunol 30(11):531–537. doi:10.1016/ PubMedCrossRefGoogle Scholar
  128. 128.
    Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666. doi:10.1056/NEJMoa051424 PubMedCrossRefGoogle Scholar
  129. 129.
    Camus M, Tosolini M, Mlecnik B, Pages F, Kirilovsky A, Berger A, Costes A, Bindea G, Charoentong P, Bruneval P, Trajanoski Z, Fridman WH, Galon J (2009) Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res 69(6):2685–2693. doi:10.1158/0008-5472.CAN-08-2654 PubMedCrossRefGoogle Scholar
  130. 130.
    Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman WH, Cadranel J (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26(27):4410–4417. doi:10.1200/JCO.2007.15.0284 PubMedCrossRefGoogle Scholar
  131. 131.
    Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF (2009) Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 69(7):3077–3085. doi:10.1158/0008-5472.CAN-08-2281 PubMedCrossRefGoogle Scholar
  132. 132.
    Benencia F, Courreges MC, Conejo-Garcia JR, Mohamed-Hadley A, Zhang L, Buckanovich RJ, Carroll R, Fraser N, Coukos G (2005) HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer. Mol Ther 12(5):789–802. doi:10.1016/j.ymthe.2005.03.026 PubMedCrossRefGoogle Scholar
  133. 133.
    Panelli MC, Stashower ME, Slade HB, Smith K, Norwood C, Abati A, Fetsch P, Filie A, Walters SA, Astry C, Arico E, Zhao Y, Selleri S, Wang E, Marincola FM (2007) Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection. Genome Biol 8 (1):R8. doi:10.1186/gb-2007-8-1-r8
  134. 134.
    Reeve J, Einecke G, Mengel M, Sis B, Kayser N, Kaplan B, Halloran PF (2009) Diagnosing rejection in renal transplants: a comparison of molecular- and histopathology-based approaches. Am J Transplant 9(8):1802–1810. doi:10.1111/j.1600-6143.2009.02694.x PubMedCrossRefGoogle Scholar
  135. 135.
    Saint-Mezard P, Berthier CC, Zhang H, Hertig A, Kaiser S, Schumacher M, Wieczorek G, Bigaud M, Kehren J, Rondeau E, Raulf F, Marti HP (2009) Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection. Transpl Int 22(3):293–302. doi:10.1111/j.1432-2277.2008.00790.x PubMedCrossRefGoogle Scholar
  136. 136.
    Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Masek M, Salvatierra O Jr (2003) Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 349(2):125–138. doi:10.1056/NEJMoa035588 PubMedCrossRefGoogle Scholar
  137. 137.
    Karason K, Jernas M, Hagg DA, Svensson PA (2006) Evaluation of CXCL9 and CXCL10 as circulating biomarkers of human cardiac allograft rejection. BMC Cardiovasc Disord 6:29. doi:10.1186/1471-2261-6-29 PubMedCrossRefGoogle Scholar
  138. 138.
    Hardstedt M, Finnegan CP, Kirchhof N, Hyland KA, Wijkstrom M, Murtaugh MP, Hering BJ (2005) Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts. Xenotransplantation 12(4):293–302. doi:10.1111/j.1399-3089.2005.00228.x PubMedCrossRefGoogle Scholar
  139. 139.
    Imanguli MM, Swaim WD, League SC, Gress RE, Pavletic SZ, Hakim FT (2009) Increased T-bet + cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa. Blood 113(15):3620–3630. doi:10.1182/blood-2008-07-168351 PubMedCrossRefGoogle Scholar
  140. 140.
    Nanda S, Havert MB, Calderon GM, Thomson M, Jacobson C, Kastner D, Liang TJ (2008) Hepatic transcriptome analysis of hepatitis C virus infection in chimpanzees defines unique gene expression patterns associated with viral clearance. PLoS One 3 (10):e3442. doi:10.1371/journal.pone.0003442
  141. 141.
    Bigger CB, Brasky KM, Lanford RE (2001) DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 75(15):7059–7066. doi:10.1128/JVI.75.15.7059-7066.2001 PubMedCrossRefGoogle Scholar
  142. 142.
    Asselah T, Bieche I, Sabbagh A, Bedossa P, Moreau R, Valla D, Vidaud M, Marcellin P (2009) Gene expression and hepatitis C virus infection. Gut 58(6):846–858. doi:10.1136/gut.2008.166348 PubMedCrossRefGoogle Scholar
  143. 143.
    He XS, Ji X, Hale MB, Cheung R, Ahmed A, Guo Y, Nolan GP, Pfeffer LM, Wright TL, Risch N, Tibshirani R, Greenberg HB (2006) Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race. Hepatology 44(2):352–359. doi:10.1002/hep.21267 PubMedCrossRefGoogle Scholar
  144. 144.
    Okamoto Y, Folco EJ, Minami M, Wara AK, Feinberg MW, Sukhova GK, Colvin RA, Kihara S, Funahashi T, Luster AD, Libby P (2008) Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis. Circ Res 102(2):218–225. doi:10.1161/CIRCRESAHA.107.164988 PubMedCrossRefGoogle Scholar
  145. 145.
    Costa C, Rufino R, Traves SL, Lapa ESJR, Barnes PJ, Donnelly LE (2008) CXCR3 and CCR5 chemokines in induced sputum from patients with COPD. Chest 133(1):26–33. doi:10.1378/chest.07-0393 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Laboratory of Lymphocyte Function, Department of Biochemistry and Cancer Biology, School of MedicineMeharry Medical CollegeNashvilleUSA
  2. 2.Department of Cancer Biology, Vanderbilt-Ingram Cancer CenterVanderbilt UniversityNashvilleUSA
  3. 3.Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and the Trans-NIH Center for Human Immunology (CHI)National Institutes of HealthBethesdaUSA

Personalised recommendations