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Basic Rules of T Cell Migration

  • Jens V. SteinEmail author
  • Federica Moalli
  • Markus Ackerknecht
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 9)

Abstract

The positive correlation of lymphocyte infiltration into solid tumors with the patient survival, as well as recent successes of checkpoint inhibitors enhancing antitumor responses, have kindled a huge interest in cancer immunotherapy. In fact, adoptive cell therapy (ACT) of tumor-recognizing T cells has led to complete recession of tumors in a subset of melanoma patients. Yet, the molecular mechanisms that guide T cells to infiltrate tumor tissue for the detection and destruction of cancer cells are only incompletely understood. Here, we will give an overview on the basic rules of T cell migration, focusing on extra- and intracellular guidance cues gained primarily from intravital two photon imaging, and relate this with the efficient unfolding of adaptive immune responses. From this, we outline the challenges that T cells face entering and maneuvering inside non-lymphoid tissues including tumor sites.

Keywords

T cell trafficking Integrins Small GTPases Intravital imaging Extracellular matrix Guanine exchange factors 

Abbreviations

ACT

Adoptive cell therapy

APC

Antigen-presenting cell

ATX

Autotaxin

DC

Dendritic cell

ECM

Extracellular matrix

FRC

Fibroblastic reticular cell

GALT

Gut-associated lymphoid tissue

GEF

Guanine exchange factor

GPCR

G-protein coupled receptor

HEV

High endothelial venule

LN

Lymph node

LPA

Lysophosphatidic acid

SLO

Secondary lymphoid organ

TIL

Tumor-infiltrating lymphocyte

Notes

Acknowledgements

The Stein laboratory is funded by Swiss National Foundation grants 31003A_135649, CR23I3_156234 and CRSII3_141918, and Swiss Cancer League grant KFS-3524-08-2014.

No Conflict Statement No potential conflicts of interest were disclosed.

References

  1. 1.
    Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, Earl HM, Poole CJ, Hiller L, Dunn JA, Bowden SJ, Twelves C, Bartlett JMS, Mahmoud SMA, Rakha E, Ellis IO, Liu S, Gao D, Nielsen TO, Pharoah PDP, Caldas C. Association between CD8+ T-cell infiltration and breast cancer survival in 12 439 patients. Ann Oncol. 2014;25(8):1536–43. doi: 10.1093/annonc/mdu191.PubMedCrossRefGoogle Scholar
  2. 2.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc P-H, Trajanoski Z, Fridman W-H, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4. doi: 10.1126/science.1129139.PubMedCrossRefGoogle Scholar
  3. 3.
    Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, Ranta F, Ullrich S, Mocikat R, Braungart K, Mehra T, Fehrenbacher B, Berdel J, Niessner H, Meier F, van den Broek M, Häring H-U, Handgretinger R, Quintanilla-Martinez L, Fend F, Pesic M, Bauer J, Zender L, Schaller M, Schulze-Osthoff K, Röcken M. T-helper-1-cell cytokines drive cancer into senescence. Nature. 2013;494:361–5. doi: 10.1038/nature11824.PubMedCrossRefGoogle Scholar
  4. 4.
    Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity. 2013;39:11–26. doi: 10.1016/j.immuni.2013.07.008.PubMedCrossRefGoogle Scholar
  5. 5.
    Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836–48. doi: 10.1038/nri1961.PubMedCrossRefGoogle Scholar
  6. 6.
    DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012;482:405–9. doi: 10.1038/nature10803.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. doi: 10.1016/j.immuni.2013.07.012.PubMedCrossRefGoogle Scholar
  8. 8.
    Couzin-Frankel J. Cancer immunotherapy. Science. 2013;342:1432–3. doi: 10.1126/science.342.6165.1432.PubMedCrossRefGoogle Scholar
  9. 9.
    Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE. Reversal of the TCR stop signal by CTLA-4. Science. 2006;313:1972–5. doi: 10.1126/science.1131078.PubMedCrossRefGoogle Scholar
  10. 10.
    Honda T, Egen JG, Lämmermann T, Kastenmuller W, Torabi-Parizi P, Germain RN. Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity. 2014;40:235–47. doi: 10.1016/j.immuni.2013.11.017.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Masopust D, Schenkel JM. The integration of T cell migration, differentiation and function. Nat Rev Immunol. 2013;13:309–20. doi: 10.1038/nri3442.PubMedCrossRefGoogle Scholar
  12. 12.
    Textor J, Henrickson SE, Mandl JN, Von Andrian UH, Westermann J, De Boer RJ, Beltman JB. Random migration and signal integration promote rapid and robust T cell recruitment. PLoS Comput Biol. 2014;10, e1003752. doi: 10.1371/journal.pcbi.1003752.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol. 2005;23:127–59. doi: 10.1146/annurev.immunol.23.021704.115628.PubMedCrossRefGoogle Scholar
  14. 14.
    Von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev Immunol. 2003;3:867–78. doi: 10.1038/nri1222.CrossRefGoogle Scholar
  15. 15.
    Shulman Z, Shinder V, Klein E, Grabovsky V, Yeger O, Geron E, Montresor A, Bolomini-Vittori M, Feigelson SW, Kirchhausen T, Laudanna C, Shakhar G, Alon R. Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin. Immunity. 2009;30:384–96. doi: 10.1016/j.immuni.2008.12.020.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bajénoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity. 2006;25:989–1001. doi: 10.1016/j.immuni.2006.10.011.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Boscacci RT, Pfeiffer F, Gollmer K, Sevilla AIC, Martin AM, Soriano SF, Natale D, Henrickson S, Von Andrian UH, Fukui Y, Mellado M, Deutsch U, Engelhardt B, Stein JV. Comprehensive analysis of lymph node stroma-expressed Ig superfamily members reveals redundant and nonredundant roles for ICAM-1, ICAM-2, and VCAM-1 in lymphocyte homing. Blood. 2010;116:915–25. doi: 10.1182/blood-2009-11-254334.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Katakai T, Habiro K, Kinashi T. Dendritic cells regulate high-speed interstitial T cell migration in the lymph node via LFA-1/ICAM-1. J Immunol. 2013;191:1188–99. doi: 10.4049/jimmunol.1300739.PubMedCrossRefGoogle Scholar
  19. 19.
    Chang JE, Turley SJ. Stromal infrastructure of the lymph node and coordination of immunity. Trends Immunol. 2015;36:30–9. doi: 10.1016/j.it.2014.11.003.PubMedCrossRefGoogle Scholar
  20. 20.
    Wendland M, Willenzon S, Kocks J, Davalos-Misslitz AC, Hammerschmidt SI, Schumann K, Kremmer E, Sixt M, Hoffmeyer A, Pabst O, Förster R. Lymph node T cell homeostasis relies on steady state homing of dendritic cells. Immunity. 2011;35:945–57. doi: 10.1016/j.immuni.2011.10.017.PubMedCrossRefGoogle Scholar
  21. 21.
    Asperti-Boursin F, Real E, Bismuth G, Trautmann A, Donnadieu E. CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3-kinase-independent manner. J Exp Med. 2007;204:1167–79. doi: 10.1084/jem.20062079.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Okada T, Cyster J. CC chemokine receptor 7 contributes to Gi-dependent T cell motility in the lymph node. J Immunol. 2007;178:2973.PubMedCrossRefGoogle Scholar
  23. 23.
    Worbs T, Mempel TR, Bölter J, Von Andrian UH, Förster R. CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J Exp Med. 2007;204:489–95. doi: 10.1084/jem.20061706.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Hwang I, Park C, Kehrl J. Impaired trafficking of Gnai2+/- and Gnai2-/- T lymphocytes: implications for T cell movement within lymph nodes. J Immunol. 2007;179:439.PubMedCrossRefGoogle Scholar
  25. 25.
    Bai Z, Cai L, Umemoto E, Takeda A, Tohya K, Komai Y, Veeraveedu PT, Hata E, Sugiura Y, Kubo A, Suematsu M, Hayasaka H, Okudaira S, Aoki J, Tanaka T, Albers HMHG, Ovaa H, Miyasaka M. Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis. J Immunol. 2013;190:2036–48. doi: 10.4049/jimmunol.1202025.PubMedCrossRefGoogle Scholar
  26. 26.
    Kanda H, Newton R, Klein R, Morita Y, Gunn MD, Rosen SD. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol. 2008;9:415–23. doi: 10.1038/ni1573.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Katakai T, Kondo N, Ueda Y, Kinashi T. Autotaxin produced by stromal cells promotes LFA-1-independent and rho-dependent interstitial T cell motility in the lymph node paracortex. J Immunol. 2014;193:617–26. doi: 10.4049/jimmunol.1400565.PubMedCrossRefGoogle Scholar
  28. 28.
    Knowlden SA, Capece T, Popovic M, Chapman TJ, Rezaee F, Kim M, Georas SN. Regulation of T cell motility in vitro and in vivo by LPA and LPA2. PLoS One. 2014;9, e101655. doi: 10.1371/journal.pone.0101655.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Zhang Y, Chen Y-CM, Krummel MF, Rosen SD. Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells. J Immunol. 2012;189:3914–24. doi: 10.4049/jimmunol.1201604.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Liu Y-J, Le Berre M, Lautenschlaeger F, Maiuri P, Callan-Jones A, Heuzé M, Takaki T, Voituriez R, Piel M. Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells. Cell. 2015;160:659–72. doi: 10.1016/j.cell.2015.01.007.PubMedCrossRefGoogle Scholar
  31. 31.
    Ruprecht V, Wieser S, Callan-Jones A, Smutny M, Morita H, Sako K, Barone V, Ritsch-Marte M, Sixt M, Voituriez R, Heisenberg C-P. Cortical contractility triggers a stochastic switch to fast amoeboid cell motility. Cell. 2015;160:673–85. doi: 10.1016/j.cell.2015.01.008.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol. 2007;8:1295–301. doi: 10.1038/ni1545.PubMedCrossRefGoogle Scholar
  33. 33.
    Shiow LR, Rosen DB, Brdicková N, Xu Y, An J, Lanier LL, Cyster JG, Matloubian M. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature. 2006;440:540–4. doi: 10.1038/nature04606.PubMedCrossRefGoogle Scholar
  34. 34.
    Lämmermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Söldner R, Hirsch K, Keller M, Förster R, Critchley DR, Fässler R, Sixt M. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature. 2008;453:51–5. doi: 10.1038/nature06887.PubMedCrossRefGoogle Scholar
  35. 35.
    Krummel MF, Macara I. Maintenance and modulation of T cell polarity. Nat Immunol. 2006;7:1143–9. doi: 10.1038/ni1404.PubMedCrossRefGoogle Scholar
  36. 36.
    Real E, Faure S, Donnadieu E, Delon J. Cutting edge: atypical PKCs regulate T lymphocyte polarity and scanning behavior. J Immunol. 2007;179:5649–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Latek D, Modzelewska A, Trzaskowski B, Palczewski K, Filipek S. G protein-coupled receptors—recent advances. Acta Biochim Pol. 2012;59:515–29. doi: 10.1016/j.jhazmat.2004.10.008.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Thelen M, Stein J. How chemokines invite leukocytes to dance. Nat Immunol. 2008;9:953–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Kehrl JH. Chemoattractant receptor signaling and the control of lymphocyte migration. Immunol Res. 2006;34:211–27. doi: 10.1385/IR:34:3:211.PubMedCrossRefGoogle Scholar
  40. 40.
    Barberis L, Pasquali C, Bertschy-Meier D, Cuccurullo A, Costa C, Ambrogio C, Vilbois F, Chiarle R, Wymann M, Altruda F, Rommel C, Hirsch E. Leukocyte transmigration is modulated by chemokine-mediated PI3Kγ-dependent phosphorylation of vimentin. Eur J Immunol. 2009;39:1136–46. doi: 10.1002/eji.200838884.PubMedCrossRefGoogle Scholar
  41. 41.
    Tybulewicz VLJ, Henderson RB. Rho family GTPases and their regulators in lymphocytes. Nat Rev Immunol. 2009;9:630–44. doi: 10.1038/nri2606.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    del Pozo MA, Vicente-Manzanares M, Tejedor R, Serrador JM, Sánchez-Madrid F. Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur J Immunol. 1999;29:3609–20. doi:10.1002/(SICI)1521-4141(199911)29:11<3609::AID-IMMU3609>3.0.CO;2-S.PubMedCrossRefGoogle Scholar
  43. 43.
    Lammermann T, Renkawitz J, Wu X, Hirsch K, Brakebusch C, Sixt M. Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration. Blood. 2009;113:5703–10. doi: 10.1182/blood-2008-11-191882.PubMedCrossRefGoogle Scholar
  44. 44.
    Ratner S, Piechocki MP, Galy A. Role of Rho-family GTPase Cdc42 in polarized expression of lymphocyte appendages. J Leukoc Biol. 2003;73:830–40. doi: 10.1189/jlb.1001894.PubMedCrossRefGoogle Scholar
  45. 45.
    Hanley PJ, Xu Y, Kronlage M, Grobe K, Schon P, Song J, Sorokin L, Schwab A, Bahler M. Motorized RhoGAP myosin IXb (Myo9b) controls cell shape and motility. Proc Natl Acad Sci. 2010;107:12145–50. doi: 10.1073/pnas.0911986107.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Morin NA, Oakes PW, Hyun Y-M, Lee D, Chin YE, Chin EY, King MR, Springer TA, Shimaoka M, Tang JX, Reichner JS, Kim M. Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration. J Exp Med. 2008;205:195–205. doi: 10.1084/jem.20071543.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Jacobelli J, Estin Matthews M, Chen S, Krummel MF. Activated T cell trans-endothelial migration relies on myosin-IIA contractility for squeezing the cell nucleus through endothelial cell barriers. PLoS One. 2013;8, e75151. doi: 10.1371/journal.pone.0075151.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Soriano SF, Hons M, Schumann K, Kumar V, Dennier TJ, Lyck R, Sixt M, Stein JV. In vivo analysis of uropod function during physiological T cell trafficking. J Immunol. 2011;187:2356–64. doi: 10.4049/jimmunol.1100935.PubMedCrossRefGoogle Scholar
  49. 49.
    Goley ED, Welch MD. The ARP2/3 complex: an actin nucleator comes of age. Nat Rev Mol Cell Biol. 2006;7:713–26. doi: 10.1038/nrm2026.PubMedCrossRefGoogle Scholar
  50. 50.
    Krummel MF, Friedman RS, Jacobelli J. Modes and mechanisms of T cell motility: roles for confinement and Myosin-IIA. Curr Opin Cell Biol. 2014;30C:9–16. doi: 10.1016/j.ceb.2014.05.003.CrossRefGoogle Scholar
  51. 51.
    Vicente-Manzanares M, Sánchez-Madrid F. Role of the cytoskeleton during leukocyte responses. Nat Rev Immunol. 2004;4:110–22. doi: 10.1038/nri1268.PubMedCrossRefGoogle Scholar
  52. 52.
    DerMardirossian C, Bokoch GM. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 2005;15:356–63. doi: 10.1016/j.tcb.2005.05.001.CrossRefPubMedGoogle Scholar
  53. 53.
    Rougerie P, Delon J. Rho GTPases: masters of T lymphocyte migration and activation. Immunol Lett. 2012;142:1–13. doi: 10.1016/j.imlet.2011.12.003.PubMedCrossRefGoogle Scholar
  54. 54.
    Nishikimi A, Kukimoto-Niino M, Yokoyama S, Fukui Y. Immune regulatory functions of DOCK family proteins in health and disease. Exp Cell Res. 2013;319:2343–9. doi: 10.1016/j.yexcr.2013.07.024.PubMedCrossRefGoogle Scholar
  55. 55.
    Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T, Hanawa-Suetsugu K, Kukimoto-Niino M, Nishizaki T, Shirouzu M, Duan X, Uruno T, Nishikimi A, Sanematsu F, Yokoyama S, Stein JV, Kinashi T, Fukui Y. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood. 2012;119:4451–61. doi: 10.1182/blood-2012-01-407098.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Zhang Q, Dove CG, Hor JL, Murdock HM, Strauss-Albee DM, Garcia JA, Mandl JN, Grodick RA, Jing H, Chandler-Brown DB, Lenardo TE, Crawford G, Matthews HF, Freeman AF, Cornall RJ, Germain RN, Mueller SN, Su HC. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J Exp Med. 2014;211(13):2549–66. doi: 10.1084/jem.20141307.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, Matthews HF, Davis J, Turner ML, Uzel G, Holland SM, Su HC. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361:2046–55. doi: 10.1056/NEJMoa0905506.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Fukui Y, Hashimoto O, Sanui T, Oono T, Koga H, Abe M, Inayoshi A, Noda M, Oike M, Shirai T. Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature. 2001;412:826–31.PubMedCrossRefGoogle Scholar
  59. 59.
    Faroudi M, Hons M, Zachacz A, Dumont C, Lyck R, Stein JV, Tybulewicz VLJ. Critical roles for Rac GTPases in T-cell migration to and within lymph nodes. Blood. 2010;116:5536–47. doi: 10.1182/blood-2010-08-299438.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Nombela-Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, Hirsch E, Martínez-A C, Fukui Y, Von Andrian UH, Stein JV. A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress. J Exp Med. 2007;204:497–510. doi: 10.1084/jem.20061780.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Dobbs K, Domínguez Conde C, Zhang S-Y, Parolini S, Audry M, Chou J, Haapaniemi E, Keles S, Bilic I, Okada S, Massaad MJ, Rounioja S, Alwahadneh AM, Serwas NK, Capuder K, Çiftçi E, Felgentreff K, Ohsumi TK, Pedergnana V, Boisson B, Haskoloğlu Ş, Ensari A, Schuster M, Moretta A, Itan Y, Patrizi O, Rozenberg F, Lebon P, Saarela J, Knip M, Petrovski S, Goldstein DB, Parrott RE, Savas B, Schambach A, Tabellini G, Bock C, Chatila TA, Comeau AM, Geha RS, Abel L, Buckley RH, İkincioğulları A, Al-Herz W, Helminen M, Doğu F, Casanova J-L, Boztuğ K, Notarangelo LD. Inherited DOCK2 deficiency in patients with early-onset invasive infections. N Engl J Med. 2015;372:2409–22. doi: 10.1056/NEJMoa1413462.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Shulman Z, Pasvolsky R, Woolf E, Grabovsky V, Feigelson SW, Erez N, Fukui Y, Alon R. DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration. Blood. 2006;108:2150–8. doi: 10.1182/blood-2006-04-017608.PubMedCrossRefGoogle Scholar
  63. 63.
    Donnadieu E, Bismuth G, Trautmann A. Antigen recognition by helper T cells elicits a sequence of distinct changes of their shape and intracellular calcium. Curr Biol. 1994;4:584–95.PubMedCrossRefGoogle Scholar
  64. 64.
    Negulescu PA, Krasieva TB, Khan A, Kerschbaum HH, Cahalan MD. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity. 1996;4:421–30.PubMedCrossRefGoogle Scholar
  65. 65.
    Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. The immunological synapse: a molecular machine controlling T cell activation. Science. 1999;285:221–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Le Floc’h A, Tanaka Y, Bantilan NS, Voisinne G, Altan-Bonnet G, Fukui Y, Huse M. Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse. J Exp Med. 2013;210:2721–37. doi: 10.1016/j.cub.2005.12.024.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol. 2009;10:1185–92. doi: 10.1038/ni.1790.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Pentcheva-Hoang T, Simpson TR, Montalvo-Ortiz W, Allison JP. Cytotoxic T lymphocyte antigen-4 blockade enhances antitumor immunity by stimulating melanoma-specific T-cell motility. Cancer Immunol Res. 2014;2:970–80. doi: 10.1158/2326-6066.CIR-14-0104.PubMedCrossRefGoogle Scholar
  69. 69.
    Zinselmeyer BH, Heydari S, Sacristan C, Nayak D, Cammer M, Herz J, Cheng X, Davis SJ, Dustin ML, McGavern DB. PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis. J Exp Med. 2013;210(4):757–74. doi: 10.1084/jem.20121416.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kupper TS, Fuhlbrigge RC, Kieffer JD, Armerding D. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature. 1997;389:978–81. doi: 10.1038/40166.PubMedCrossRefGoogle Scholar
  71. 71.
    Smithson G, Rogers CE, Smith PL, Scheidegger EP, Petryniak B, Myers JT, Kim DSL, Homeister JW, Lowe JB. Fuc-Tvii is required for T helper 1 and T cytotoxic 1 lymphocyte selectin ligand expression and recruitment in inflammation, and together with Fuc-Tiv regulates naive T cell trafficking to lymph nodes. J Exp Med. 2001;194:601–14. doi: 10.1016/1074-7613(94)90041-8.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Mora JR, Iwata M, Von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008;8:685–98. doi: 10.1038/nri2378.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Mora JR, Von Andrian UH. T-cell homing specificity and plasticity: new concepts and future challenges. Trends Immunol. 2006;27:235–43. doi: 10.1016/j.it.2006.03.007.PubMedCrossRefGoogle Scholar
  74. 74.
    Hammerschmidt SI, Ahrendt M, Bode U, Wahl B, Kremmer E, Forster R, Pabst O. Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo. J Exp Med. 2008;205:2483–90. doi: 10.1084/jem.20080039.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC. DCs metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol. 2007;8:285–93. doi: 10.1038/ni1433.PubMedCrossRefGoogle Scholar
  76. 76.
    Calzascia T, Masson F, Di Berardino-Besson W, Contassot E, Wilmotte R, Aurrand-Lions M, Rüegg C, Dietrich P-Y, Walker PR. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity. 2005;22:175–84. doi: 10.1016/j.immuni.2004.12.008.PubMedCrossRefGoogle Scholar
  77. 77.
    Sandoval F, Terme M, Nizard M, Badoual C, Bureau M-F, Freyburger L, Clement O, Marcheteau E, Gey A, Fraisse G, Bouguin C, Merillon N, Dransart E, Tran T, Quintin-Colonna F, Autret G, Thiebaud M, Suleman M, Riffault S, Wu T-C, Launay O, Danel C, Taieb J, Richardson J, Zitvogel L, Fridman WH, Johannes L, Tartour E. Mucosal imprinting of vaccine-induced CD8+ T cells is crucial to inhibit the growth of mucosal tumors. Sci Transl Med. 2013;5:172ra20. doi: 10.1126/scitranslmed.3004888.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63. doi: 10.1146/annurev.immunol.22.012703.104702.PubMedCrossRefGoogle Scholar
  79. 79.
    Farber DL, Yudanin NA, Restifo NP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol. 2014;14:24–35. doi: 10.1038/nri3567.PubMedCrossRefGoogle Scholar
  80. 80.
    Ariotti S, Beltman JB, Chodaczek G, Hoekstra ME, van Beek AE, Gomez-Eerland R, Ritsma L, van Rheenen J, Marée AFM, Zal T, De Boer RJ, Haanen JBAG, Schumacher TN. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc Natl Acad Sci. 2012;109:19739–44. doi: 10.1073/pnas.1208927109.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature. 2011;477:216–9. doi: 10.1038/nature10339.PubMedCrossRefGoogle Scholar
  82. 82.
    Egen JG, Rothfuchs AG, Feng CG, Winter N, Sher A, Germain RN. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity. 2008;28:271–84. doi: 10.1016/j.immuni.2007.12.010.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun Y-M, Lambert K, Acharya M, Billroth-MacLurg AC, Rosenberg AF, Topham DJ, Yagita H, Kim M, Lacy-Hulbert A, Meier-Schellersheim M, Fowell DJ. Inflammation-induced interstitial migration of effector CD4+ T cells is dependent on integrin αV. Nat Immunol. 2013;14:949–58. doi: 10.1038/ni.2682.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Friedl P, Zänker K, Bröcker E. Cell migration strategies in 3-D extracellular matrix: differences in morphology, cell matrix interactions, and integrin function. Microsc Res Tech. 1998;43:369–78.PubMedCrossRefGoogle Scholar
  85. 85.
    Preston GC, Feijoo-Carnero C, Schurch N, Cowling VH, Cantrell DA. The impact of KLF2 modulation on the transcriptional program and function of CD8 T cells. PLoS One. 2013;8, e77537. doi: 10.1371/journal.pone.0077537.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, Ku AW, Frelinger JG, Odunsi K, Gajewski TF, Luster AD, Evans SS. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun. 2015;6:1–14. doi: 10.1038/ncomms8458.Google Scholar
  87. 87.
    Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74(24):7168–74. doi: 10.1158/0008-5472.CAN-14-2458.PubMedCrossRefGoogle Scholar
  88. 88.
    Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. 2014;32:659–702. doi: 10.1146/annurev-immunol-032713-120145.PubMedCrossRefGoogle Scholar
  89. 89.
    Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon M-L, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat Immunol. 2013;14:1294–301. doi: 10.1038/ni.2744.PubMedCrossRefGoogle Scholar
  90. 90.
    Shin H, Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature. 2012;491:463–7. doi: 10.1038/nature11522.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Hickman HD, Reynoso GV, Ngudiankama BF, Cush SS, Gibbs J, Bennink JR, Yewdell JW. CXCR3 chemokine receptor enables local CD8(+) T cell migration for the destruction of virus-infected cells. Immunity. 2015;42:524–37. doi: 10.1016/j.immuni.2015.02.009.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Zaid A, Mackay LK, Rahimpour A, Braun A, Veldhoen M, Carbone FR, Manton JH, Heath WR, Mueller SN. Persistence of skin-resident memory T cells within an epidermal niche. Proc Natl Acad Sci. 2014;111:5307–12. doi: 10.1073/pnas.1322292111.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36:265–76. doi: 10.1016/j.it.2015.02.008.PubMedCentralCrossRefPubMedGoogle Scholar
  94. 94.
    Kusmartsev S, Nagaraj S, Gabrilovich DI. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol. 2005;175:4583–92. doi: 10.4049/jimmunol.175.7.4583.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Sotomayor EM, Borrello I, Rattis FM, Cuenca AG, Abrams J, Staveley-O’Carroll K, Levitsky HI. Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood. 2001;98:1070–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74. doi: 10.1038/nri2506.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9:259–70. doi: 10.1038/nri2528.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Engelhardt JJ, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C, Werb Z, Egeblad M, Krummel MF. Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell. 2012;21:402–17. doi: 10.1016/j.ccr.2012.01.008.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Bauer CA, Kim EY, Marangoni F, Carrizosa E, Claudio NM, Mempel TR. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest. 2014;124(6):2425–40. doi: 10.1172/JCI66375.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Boissonnas A, Fetler L, Zeelenberg IS, Hugues S, Amigorena S. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med. 2007;204:345–56. doi: 10.1084/jem.20061890.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Mrass P, Takano H, Ng LG, Daxini S, Lasaro MO, Iparraguirre A, Cavanagh LL, Von Andrian UH, Ertl HCJ, Haydon PG, Weninger W. Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J Exp Med. 2006;203:2749–61. doi: 10.1084/jem.20060710.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean M-C, Validire P, Trautmann A, Mami-Chouaib F, Donnadieu E. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest. 2012;122:899–910. doi: 10.1172/JCI45817DS1.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Hong M, Puaux A-L, Huang C, Loumagne L, Tow C, Mackay C, Kato M, Prévost-Blondel A, Avril M-F, Nardin A, Abastado J-P. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 2011;71:6997–7009. doi: 10.1158/0008-5472.CAN-11-1466.PubMedCrossRefGoogle Scholar
  104. 104.
    Zumwalt TJ, Arnold M, Goel A, Boland CR. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration. Oncotarget. 2015;6:2981–91.PubMedCrossRefGoogle Scholar
  105. 105.
    Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan SK, Cowley GS, Elpek K, Brogdon J, Lamb J, Turley SJ, Ploegh HL, Root DE, Love JC, Dranoff G, Hacohen N, Cantor H, Wucherpfennig KW. In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature. 2014;506:52–7. doi: 10.1038/nature12988.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Jens V. Stein
    • 1
    Email author
  • Federica Moalli
    • 1
  • Markus Ackerknecht
    • 1
    • 2
  1. 1.Theodor Kocher Institute, University of BernBernSwitzerland
  2. 2.Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland

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