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Molecular mechanisms of CD8+ T cell trafficking and localization

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Abstract

Cytotoxic CD8+ T cells are potent mediators of host protection against disease due to their ability to directly kill cells infected with intracellular pathogens and produce inflammatory cytokines at the site of infection. To fully achieve this objective, naïve CD8+ T cells must be able to survey the entire body for the presence of foreign or “non-self” antigen that is delivered to draining lymph nodes following infection or tissue injury. Once activated, CD8+ T cells undergo many rounds of cell division, acquire effector functions, and are no longer restricted to the circulation and lymphoid compartments like their naïve counterparts, but rather are drawn to inflamed tissues to combat infection. As CD8+ T cells transition from naïve to effector to memory populations, this is accompanied by dynamic changes in the expression of adhesion molecules and chemokine receptors that ultimately dictate their localization in vivo. Thus, an understanding of the molecular mechanisms regulating CD8+ T cell trafficking and localization is critical for vaccine design, control of infectious diseases, treatment of autoimmune disorders, and cancer immunotherapy.

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References

  1. Zhang N, Bevan MJ (2011) CD8(+) T cells: foot soldiers of the immune system. Immunity 35(2):161–168. doi:10.1016/j.immuni.2011.07.010

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Harty JT, Tvinnereim AR, White DW (2000) CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol 18:275–308. doi:10.1146/annurev.immunol.18.1.275

    CAS  PubMed  Google Scholar 

  3. Harty JT, Badovinac VP (2008) Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol 8(2):107–119. doi:10.1038/nri2251

    CAS  PubMed  Google Scholar 

  4. Butler NS, Nolz JC, Harty JT (2011) Immunologic considerations for generating memory CD8 T cells through vaccination. Cell Microbiol 13(7):925–933. doi:10.1111/j.1462-5822.2011.01594.x

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Kaech SM, Wherry EJ, Ahmed R (2002) Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2(4):251–262. doi:10.1038/nri778

    CAS  PubMed  Google Scholar 

  6. Klebanoff CA, Gattinoni L, Restifo NP (2006) CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol Rev 211:214–224. doi:10.1111/j.0105-2896.2006.00391.x

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Melero I, Rouzaut A, Motz GT, Coukos G (2014) T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer discovery 4(5):522–526. doi:10.1158/2159-8290.CD-13-0985

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964. doi:10.1126/science.1129139

    CAS  PubMed  Google Scholar 

  9. Newell EW, Sigal N, Bendall SC, Nolan GP, Davis MM (2012) Cytometry by time-of-flight shows combinatorial cytokine expression and virus-specific cell niches within a continuum of CD8+ T cell phenotypes. Immunity 36(1):142–152. doi:10.1016/j.immuni.2012.01.002

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Chen G, Shankar P, Lange C, Valdez H, Skolnik PR, Wu L, Manjunath N, Lieberman J (2001) CD8 T cells specific for human immunodeficiency virus, Epstein-Barr virus, and cytomegalovirus lack molecules for homing to lymphoid sites of infection. Blood 98(1):156–164

    CAS  PubMed  Google Scholar 

  11. Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM (2013) Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 38(2):373–383. doi:10.1016/j.immuni.2012.10.021

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Miller JD, van der Most RG, Akondy RS, Glidewell JT, Albott S, Masopust D, Murali-Krishna K, Mahar PL, Edupuganti S, Lalor S, Germon S, Del Rio C, Mulligan MJ, Staprans SI, Altman JD, Feinberg MB, Ahmed R (2008) Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 28(5):710–722. doi:10.1016/j.immuni.2008.02.020

    CAS  PubMed  Google Scholar 

  13. Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD, Gruener N, Pape G, Waters A, Easterbrook P, Salio M, Cerundolo V, McMichael AJ, Rowland-Jones SL (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8(4):379–385. doi:10.1038/nm0402-379

    CAS  PubMed  Google Scholar 

  14. Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7(9):678–689. doi:10.1038/nri2156

    CAS  PubMed  Google Scholar 

  15. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN (2011) Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477(7363):216–219. doi:10.1038/nature10339

    CAS  PubMed  Google Scholar 

  16. Klonowski KD, Williams KJ, Marzo AL, Blair DA, Lingenheld EG, Lefrancois L (2004) Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20(5):551–562

    CAS  PubMed  Google Scholar 

  17. Obar JJ, Khanna KM, Lefrancois L (2008) Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28(6):859–869. doi:10.1016/j.immuni.2008.04.010

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Blattman JN, Antia R, Sourdive DJ, Wang X, Kaech SM, Murali-Krishna K, Altman JD, Ahmed R (2002) Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med 195(5):657–664

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Girard JP, Moussion C, Forster R (2012) HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 12(11):762–773. doi:10.1038/nri3298

    CAS  PubMed  Google Scholar 

  20. Mackay CR, Marston WL, Dudler L (1990) Naive and memory T cells show distinct pathways of lymphocyte recirculation. J Exp Med 171(3):801–817

    CAS  PubMed  Google Scholar 

  21. Bruehl RE, Bertozzi CR, Rosen SD (2000) Minimal sulfated carbohydrates for recognition by L-selectin and the MECA-79 antibody. J Biol Chem 275(42):32642–32648. doi:10.1074/jbc.M001703200

    CAS  PubMed  Google Scholar 

  22. Rosen SD (2004) Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 22:129–156. doi:10.1146/annurev.immunol.21.090501.080131

    CAS  PubMed  Google Scholar 

  23. Umemoto E, Tanaka T, Kanda H, Jin S, Tohya K, Otani K, Matsutani T, Matsumoto M, Ebisuno Y, Jang MH, Fukuda M, Hirata T, Miyasaka M (2006) Nepmucin, a novel HEV sialomucin, mediates L-selectin-dependent lymphocyte rolling and promotes lymphocyte adhesion under flow. J Exp Med 203(6):1603–1614. doi:10.1084/jem.20052543

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Mitoma J, Bao X, Petryanik B, Schaerli P, Gauguet JM, Yu SY, Kawashima H, Saito H, Ohtsubo K, Marth JD, Khoo KH, von Andrian UH, Lowe JB, Fukuda M (2007) Critical functions of N-glycans in L-selectin-mediated lymphocyte homing and recruitment. Nat Immunol 8(4):409–418. doi:10.1038/ni1442

    CAS  PubMed  Google Scholar 

  25. Diacovo TG, Catalina MD, Siegelman MH, von Andrian UH (1998) Circulating activated platelets reconstitute lymphocyte homing and immunity in L-selectin-deficient mice. J Exp Med 187(2):197–204

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Diacovo TG, Puri KD, Warnock RA, Springer TA, von Andrian UH (1996) Platelet-mediated lymphocyte delivery to high endothelial venules. Science 273(5272):252–255

    CAS  PubMed  Google Scholar 

  27. Allen SJ, Crown SE, Handel TM (2007) Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25:787–820. doi:10.1146/annurev.immunol.24.021605.090529

    CAS  PubMed  Google Scholar 

  28. Zlotnik A, Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12(2):121–127

    CAS  PubMed  Google Scholar 

  29. Neves SR, Ram PT, Iyengar R (2002) G protein pathways. Science 296(5573):1636–1639. doi:10.1126/science.1071550

    CAS  PubMed  Google Scholar 

  30. Forster R, Davalos-Misslitz AC, Rot A (2008) CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8(5):362–371. doi:10.1038/nri2297

    PubMed  Google Scholar 

  31. Baekkevold ES, Yamanaka T, Palframan RT, Carlsen HS, Reinholt FP, von Andrian UH, Brandtzaeg P, Haraldsen G (2001) The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J Exp Med 193(9):1105–1112

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Bao X, Moseman EA, Saito H, Petryniak B, Thiriot A, Hatakeyama S, Ito Y, Kawashima H, Yamaguchi Y, Lowe JB, von Andrian UH, Fukuda M (2010) Endothelial heparan sulfate controls chemokine presentation in recruitment of lymphocytes and dendritic cells to lymph nodes. Immunity 33(5):817–829. doi:10.1016/j.immuni.2010.10.018

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Kinashi T (2005) Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 5(7):546–559. doi:10.1038/nri1646

    CAS  PubMed  Google Scholar 

  34. Warnock RA, Askari S, Butcher EC, von Andrian UH (1998) Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J Exp Med 187(2):205–216

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Park EJ, Peixoto A, Imai Y, Goodarzi A, Cheng G, Carman CV, von Andrian UH, Shimaoka M (2010) Distinct roles for LFA-1 affinity regulation during T-cell adhesion, diapedesis, and interstitial migration in lymph nodes. Blood 115(8):1572–1581. doi:10.1182/blood-2009-08-237917

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Moussion C, Girard JP (2011) Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 479(7374):542–546. doi:10.1038/nature10540

    CAS  PubMed  Google Scholar 

  37. Munoz MA, Biro M, Weninger W (2014) T cell migration in intact lymph nodes in vivo. Curr Opin Cell Biol 30:17–24. doi:10.1016/j.ceb.2014.05.002

    CAS  PubMed  Google Scholar 

  38. Okada T, Cyster JG (2007) CC chemokine receptor 7 contributes to Gi-dependent T cell motility in the lymph node. J Immunol 178(5):2973–2978

    CAS  PubMed  Google Scholar 

  39. Worbs T, Mempel TR, Bolter J, von Andrian UH, Forster R (2007) CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J Exp Med 204(3):489–495. doi:10.1084/jem.20061706

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN (2006) Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25(6):989–1001. doi:10.1016/j.immuni.2006.10.011

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Denton AE, Roberts EW, Linterman MA, Fearon DT (2014) Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells. Proc Natl Acad Sci USA 111(33):12139–12144. doi:10.1073/pnas.1412910111

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN (2006) Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440(7086):890–895. doi:10.1038/nature04651

    CAS  PubMed  Google Scholar 

  43. Mempel TR, Henrickson SE, Von Andrian UH (2004) T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427(6970):154–159. doi:10.1038/nature02238

    CAS  PubMed  Google Scholar 

  44. Henrickson SE, Mempel TR, Mazo IB, Liu B, Artyomov MN, Zheng H, Peixoto A, Flynn MP, Senman B, Junt T, Wong HC, Chakraborty AK, von Andrian UH (2008) T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat Immunol 9(3):282–291. doi:10.1038/ni1559

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Henrickson SE, Perro M, Loughhead SM, Senman B, Stutte S, Quigley M, Alexe G, Iannacone M, Flynn MP, Omid S, Jesneck JL, Imam S, Mempel TR, Mazo IB, Haining WN, von Andrian UH (2013) Antigen availability determines CD8(+) T cell-dendritic cell interaction kinetics and memory fate decisions. Immunity 39(3):496–507. doi:10.1016/j.immuni.2013.08.034

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Dustin ML, Springer TA (1989) T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature 341(6243):619–624. doi:10.1038/341619a0

    CAS  PubMed  Google Scholar 

  47. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285(5425):221–227

    CAS  PubMed  Google Scholar 

  48. Hickman HD, Takeda K, Skon CN, Murray FR, Hensley SE, Loomis J, Barber GN, Bennink JR, Yewdell JW (2008) Direct priming of antiviral CD8+ T cells in the peripheral interfollicular region of lymph nodes. Nat Immunol 9(2):155–165. doi:10.1038/ni1557

    CAS  PubMed  Google Scholar 

  49. John B, Harris TH, Tait ED, Wilson EH, Gregg B, Ng LG, Mrass P, Roos DS, Dzierszinski F, Weninger W, Hunter CA (2009) Dynamic Imaging of CD8(+) T cells and dendritic cells during infection with Toxoplasma gondii. PLoS Pathog 5(7):e1000505. doi:10.1371/journal.ppat.1000505

    PubMed Central  PubMed  Google Scholar 

  50. Mandl JN, Liou R, Klauschen F, Vrisekoop N, Monteiro JP, Yates AJ, Huang AY, Germain RN (2012) Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naive CD4+ and CD8+ T cells. Proc Natl Acad Sci USA 109(44):18036–18041. doi:10.1073/pnas.1211717109

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Tomura M, Yoshida N, Tanaka J, Karasawa S, Miwa Y, Miyawaki A, Kanagawa O (2008) Monitoring cellular movement in vivo with photoconvertible fluorescence protein “Kaede” transgenic mice. Proc Natl Acad Sci USA 105(31):10871–10876. doi:10.1073/pnas.0802278105

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Cyster JG, Schwab SR (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30:69–94. doi:10.1146/annurev-immunol-020711-075011

    CAS  PubMed  Google Scholar 

  53. Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309(5741):1735–1739. doi:10.1126/science.1113640

    CAS  PubMed  Google Scholar 

  54. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296(5566):346–349. doi:10.1126/science.1070238

    CAS  PubMed  Google Scholar 

  55. Shiow LR, Rosen DB, Brdickova N, Xu Y, An J, Lanier LL, Cyster JG, Matloubian M (2006) CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440(7083):540–544. doi:10.1038/nature04606

    CAS  PubMed  Google Scholar 

  56. Bankovich AJ, Shiow LR, Cyster JG (2010) CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4. J Biol Chem 285(29):22328–22337. doi:10.1074/jbc.M110.123299

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Chen A, Engel P, Tedder TF (1995) Structural requirements regulate endoproteolytic release of the L-selectin (CD62L) adhesion receptor from the cell surface of leukocytes. J Exp Med 182(2):519–530

    CAS  PubMed  Google Scholar 

  58. Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7(10):803–815. doi:10.1038/nri2171

    CAS  PubMed  Google Scholar 

  59. Bevilacqua MP (1993) Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 11:767–804. doi:10.1146/annurev.iy.11.040193.004003

    CAS  PubMed  Google Scholar 

  60. Middleton J, Patterson AM, Gardner L, Schmutz C, Ashton BA (2002) Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100(12):3853–3860. doi:10.1182/blood.V100.12.3853

    CAS  PubMed  Google Scholar 

  61. Carlow DA, Gossens K, Naus S, Veerman KM, Seo W, Ziltener HJ (2009) PSGL-1 function in immunity and steady state homeostasis. Immunol Rev 230(1):75–96. doi:10.1111/j.1600-065X.2009.00797.x

    CAS  PubMed  Google Scholar 

  62. Hidalgo A, Peired AJ, Wild MK, Vestweber D, Frenette PS (2007) Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44. Immunity 26(4):477–489. doi:10.1016/j.immuni.2007.03.011

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Ley K, Kansas GS (2004) Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat Rev Immunol 4(5):325–335. doi:10.1038/nri1351

    CAS  PubMed  Google Scholar 

  64. Marth JD, Grewal PK (2008) Mammalian glycosylation in immunity. Nat Rev Immunol 8(11):874–887. doi:10.1038/nri2417

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Groom JR, Luster AD (2011) CXCR3 in T cell function. Exp Cell Res 317(5):620–631. doi:10.1016/j.yexcr.2010.12.017

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Nakanishi Y, Lu B, Gerard C, Iwasaki A (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462(7272):510–513. doi:10.1038/nature08511

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Lefrancois L, Parker CM, Olson S, Muller W, Wagner N, Schon MP, Puddington L (1999) The role of beta7 integrins in CD8 T cell trafficking during an antiviral immune response. J Exp Med 189(10):1631–1638

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Ray SJ, Franki SN, Pierce RH, Dimitrova S, Koteliansky V, Sprague AG, Doherty PC, de Fougerolles AR, Topham DJ (2004) The collagen binding alpha1beta1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection. Immunity 20(2):167–179

    CAS  PubMed  Google Scholar 

  69. Ferguson AR, Engelhard VH (2010) CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors. J Immunol 184(8):4079–4086. doi:10.4049/jimmunol.0901903

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Dudda JC, Simon JC, Martin S (2004) Dendritic cell immunization route determines CD8+ T cell trafficking to inflamed skin: role for tissue microenvironment and dendritic cells in establishment of T cell-homing subsets. Journal of immunology 172(2):857–863

    CAS  Google Scholar 

  71. Liu L, Fuhlbrigge RC, Karibian K, Tian T, Kupper TS (2006) Dynamic programming of CD8+ T cell trafficking after live viral immunization. Immunity 25(3):511–520. doi:10.1016/j.immuni.2006.06.019

    CAS  PubMed  Google Scholar 

  72. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH (2003) Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424(6944):88–93. doi:10.1038/nature01726

    CAS  PubMed  Google Scholar 

  73. Mora JR, Cheng G, Picarella D, Briskin M, Buchanan N, von Andrian UH (2005) Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J Exp Med 201(2):303–316. doi:10.1084/jem.20041645

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Campbell DJ, Butcher EC (2002) Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues. J Exp Med 195(1):135–141

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Masopust D, Choo D, Vezys V, Wherry EJ, Duraiswamy J, Akondy R, Wang J, Casey KA, Barber DL, Kawamura KS, Fraser KA, Webby RJ, Brinkmann V, Butcher EC, Newell KA, Ahmed R (2010) Dynamic T cell migration program provides resident memory within intestinal epithelium. J Exp Med 207(3):553–564. doi:10.1084/jem.20090858

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Nolz JC, Harty JT (2014) IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking. J Clin Investig 124(3):1013–1026. doi:10.1172/JCI72039

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun YM, Lambert K, Acharya M, Billroth-Maclurg AC, Rosenberg AF, Topham DJ, Yagita H, Kim M, Lacy-Hulbert A, Meier-Schellersheim M, Fowell DJ (2013) Inflammation-induced interstitial migration of effector CD4(+) T cells is dependent on integrin alphaV. Nat Immunol 14(9):949–958. doi:10.1038/ni.2682

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Harris TH, Banigan EJ, Christian DA, Konradt C, Tait Wojno ED, Norose K, Wilson EH, John B, Weninger W, Luster AD, Liu AJ, Hunter CA (2012) Generalized Levy walks and the role of chemokines in migration of effector CD8+ T cells. Nature 486(7404):545–548. doi:10.1038/nature11098

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Jennrich S, Lee MH, Lynn RC, Dewberry K, Debes GF (2012) Tissue exit: a novel control point in the accumulation of antigen-specific CD8 T cells in the influenza a virus-infected lung. J Virol 86(7):3436–3445. doi:10.1128/JVI.07025-11

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Bromley SK, Thomas SY, Luster AD (2005) Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol 6(9):895–901. doi:10.1038/ni1240

    CAS  PubMed  Google Scholar 

  81. Debes GF, Arnold CN, Young AJ, Krautwald S, Lipp M, Hay JB, Butcher EC (2005) Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat Immunol 6(9):889–894. doi:10.1038/ni1238

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Ledgerwood LG, Lal G, Zhang N, Garin A, Esses SJ, Ginhoux F, Merad M, Peche H, Lira SA, Ding Y, Yang Y, He X, Schuchman EH, Allende ML, Ochando JC, Bromberg JS (2008) The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nat Immunol 9(1):42–53. doi:10.1038/ni1534

    CAS  PubMed  Google Scholar 

  83. Weng NP, Araki Y, Subedi K (2012) The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol 12(4):306–315. doi:10.1038/nri3173

    CAS  PubMed  Google Scholar 

  84. Murali-Krishna K, Altman JD, Suresh M, Sourdive DJ, Zajac AJ, Miller JD, Slansky J, Ahmed R (1998) Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8(2):177–187

    CAS  PubMed  Google Scholar 

  85. Barber DL, Wherry EJ, Ahmed R (2003) Cutting edge: rapid in vivo killing by memory CD8 T cells. J Immunol 171(1):27–31

    CAS  PubMed  Google Scholar 

  86. Schluns KS, Lefrancois L (2003) Cytokine control of memory T-cell development and survival. Nat Rev Immunol 3(4):269–279. doi:10.1038/nri1052

    CAS  PubMed  Google Scholar 

  87. Nolz JC, Starbeck-Miller GR, Harty JT (2011) Naive, effector and memory CD8 T-cell trafficking: parallels and distinctions. Immunotherapy 3(10):1223–1233. doi:10.2217/imt.11.100

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Masopust D, Vezys V, Usherwood EJ, Cauley LS, Olson S, Marzo AL, Ward RL, Woodland DL, Lefrancois L (2004) Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J Immunol 172(8):4875–4882

    CAS  PubMed  Google Scholar 

  89. Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763. doi:10.1146/annurev.immunol.22.012703.104702

    CAS  PubMed  Google Scholar 

  90. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401(6754):708–712. doi:10.1038/44385

    CAS  PubMed  Google Scholar 

  91. Nolz JC, Harty JT (2011) Protective capacity of memory CD8+ T cells is dictated by antigen exposure history and nature of the infection. Immunity 34(5):781–793. doi:10.1016/j.immuni.2011.03.020

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Jabbari A, Harty JT (2006) Secondary memory CD8+ T cells are more protective but slower to acquire a central-memory phenotype. J Exp Med 203(4):919–932. doi:10.1084/jem.20052237

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Olson JA, McDonald-Hyman C, Jameson SC, Hamilton SE (2013) Effector-like CD8(+) T cells in the memory population mediate potent protective immunity. Immunity 38(6):1250–1260. doi:10.1016/j.immuni.2013.05.009

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, von Andrian UH, Ahmed R (2003) Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 4(3):225–234. doi:10.1038/ni889

    CAS  PubMed  Google Scholar 

  95. Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, Palmer DC, Antony PA, Hwang ST, Rosenberg SA, Waldmann TA, Restifo NP (2005) Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA 102(27):9571–9576. doi:10.1073/pnas.0503726102

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Haring JS, Badovinac VP, Harty JT (2006) Inflaming the CD8+ T cell response. Immunity 25(1):19–29. doi:10.1016/j.immuni.2006.07.001

    CAS  PubMed  Google Scholar 

  97. Badovinac VP, Messingham KA, Jabbari A, Haring JS, Harty JT (2005) Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat Med 11(7):748–756. doi:10.1038/nm1257

    CAS  PubMed  Google Scholar 

  98. Ely KH, Cauley LS, Roberts AD, Brennan JW, Cookenham T, Woodland DL (2003) Nonspecific recruitment of memory CD8+ T cells to the lung airways during respiratory virus infections. J Immunol 170(3):1423–1429

    CAS  PubMed  Google Scholar 

  99. Woodland DL, Kohlmeier JE (2009) Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol 9(3):153–161. doi:10.1038/nri2496

    CAS  PubMed  Google Scholar 

  100. Kohlmeier JE, Miller SC, Smith J, Lu B, Gerard C, Cookenham T, Roberts AD, Woodland DL (2008) The chemokine receptor CCR5 plays a key role in the early memory CD8+ T cell response to respiratory virus infections. Immunity 29(1):101–113. doi:10.1016/j.immuni.2008.05.011

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Slutter B, Pewe LL, Kaech SM, Harty JT (2013) Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus. Immunity 39(5):939–948. doi:10.1016/j.immuni.2013.09.013

    CAS  PubMed  Google Scholar 

  102. Wirth TC, Xue HH, Rai D, Sabel JT, Bair T, Harty JT, Badovinac VP (2010) Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8(+) T cell differentiation. Immunity 33(1):128–140. doi:10.1016/j.immuni.2010.06.014

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Masopust D, Ha SJ, Vezys V, Ahmed R (2006) Stimulation history dictates memory CD8 T cell phenotype: implications for prime-boost vaccination. J Immunol 177(2):831–839

    CAS  PubMed  Google Scholar 

  104. Munks MW, Cho KS, Pinto AK, Sierro S, Klenerman P, Hill AB (2006) Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J Immunol 177(1):450–458

    CAS  PubMed  Google Scholar 

  105. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR (2009) Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10(5):524–530. doi:10.1038/ni.1718

    CAS  PubMed  Google Scholar 

  106. Casey KA, Fraser KA, Schenkel JM, Moran A, Abt MC, Beura LK, Lucas PJ, Artis D, Wherry EJ, Hogquist K, Vezys V, Masopust D (2012) Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J Immunol 188(10):4866–4875. doi:10.4049/jimmunol.1200402

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Laidlaw BJ, Zhang N, Marshall HD, Staron MM, Guan T, Hu Y, Cauley LS, Craft J, Kaech SM (2014) CD4(+) T cell help guides formation of CD103(+) lung-resident memory CD8(+) T cells during influenza viral infection. Immunity 41(4):633–645. doi:10.1016/j.immuni.2014.09.007

    CAS  PubMed  Google Scholar 

  108. Ariotti S, Beltman JB, Chodaczek G, Hoekstra ME, van Beek AE, Gomez-Eerland R, Ritsma L, van Rheenen J, Maree AF, Zal T, de Boer RJ, Haanen JB, Schumacher TN (2012) Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc Natl Acad Sci USA 109(48):19739–19744. doi:10.1073/pnas.1208927109

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T (2013) The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. Nat Immunol 14(12):1294–1301. doi:10.1038/ni.2744

    CAS  PubMed  Google Scholar 

  110. Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS (2012) Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 483(7388):227–231. doi:10.1038/nature10851

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Schenkel JM, Fraser KA, Beura LK, Pauken KE, Vezys V, Masopust D (2014) T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346(6205):98–101. doi:10.1126/science.1254536

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Sheridan BS, Pham QM, Lee YT, Cauley LS, Puddington L, Lefrancois L (2014) Oral infection drives a distinct population of intestinal resident memory CD8(+) T cells with enhanced protective function. Immunity 40(5):747–757. doi:10.1016/j.immuni.2014.03.007

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Cepek KL, Shaw SK, Parker CM, Russell GJ, Morrow JS, Rimm DL, Brenner MB (1994) Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 372(6502):190–193. doi:10.1038/372190a0

    CAS  PubMed  Google Scholar 

  114. Skon CN, Lee JY, Anderson KG, Masopust D, Hogquist KA, Jameson SC (2013) Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat Immunol 14(12):1285–1293. doi:10.1038/ni.2745

    CAS  PubMed  Google Scholar 

  115. Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, Mueller SN, Heath WR, Carbone FR, Gebhardt T (2012) Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci USA 109(18):7037–7042. doi:10.1073/pnas.1202288109

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Zhang N, Bevan MJ (2013) Transforming growth factor-beta signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39(4):687–696. doi:10.1016/j.immuni.2013.08.019

    PubMed Central  PubMed  Google Scholar 

  117. Vander Lugt B, Tubo NJ, Nizza ST, Boes M, Malissen B, Fuhlbrigge RC, Kupper TS, Campbell JJ (2013) CCR7 plays no appreciable role in trafficking of central memory CD4 T cells to lymph nodes. J Immunol 191(6):3119–3127. doi:10.4049/jimmunol.1200938

    CAS  PubMed  Google Scholar 

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Acknowledgments

I would like to thank Dr. Amanda Lund for helpful discussion and critical review of the manuscript. Research in the Nolz laboratory is supported by the National Institute of Health Grant K22AI102981 and the OHSU Knight Cancer Center Support Grant NIH P30-CA069533.

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  1. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, 6516 Richard Jones Hall, 3181 SW Sam Jackson Park Road, Mail Code: L220, Portland, OR, 97239, USA

    Jeffrey C. Nolz

  2. Department of Cell, Developmental, and Cancer Biology, Oregon Health and Science University, Portland, OR, 97239, USA

    Jeffrey C. Nolz

  3. Department of Radiation Medicine, Oregon Health and Science University, Portland, OR, 97239, USA

    Jeffrey C. Nolz

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Nolz, J.C. Molecular mechanisms of CD8+ T cell trafficking and localization. Cell. Mol. Life Sci. 72, 2461–2473 (2015). https://doi.org/10.1007/s00018-015-1835-0

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