Targeting resident memory T cell immunity culminates in pulmonary and systemic protection against Brucella infection

English version

Autoři: Hongbin Wang ^aff001; Carol Hoffman ^aff001; Xinghong Yang ^aff001; Beata Clapp ^aff001; David W. Pascual ^aff001
Působiště autorů: Department of Infectious Diseases and Immunology, University of Florida, Gainesville, Florida, United States of America ^aff001
Vyšlo v časopise: Targeting resident memory T cell immunity culminates in pulmonary and systemic protection against Brucella infection. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008176
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008176

Souhrn

Brucellosis remains the most common zoonotic disease globally. Currently no vaccines for humans exist, and conventional brucellosis vaccines for livestock fail to confer complete protection; hence, an improved vaccine is needed. Although Brucella infections primarily occur following a mucosal exposure, vaccines are administered parenterally. Few studies have considered mucosal vaccinations, or even targeting of tissue-resident memory T (T_RM) cells. T_RM cells protect against viral infections, but less is known of their role in bacterial infections, and even less for brucellosis. Oral prime, nasal boost with a newly developed Brucella abortus double mutant (znBAZ) confers nearly complete protection against pulmonary challenge with wild-type (wt) B. abortus 2308, and its protective efficacy is >2800-fold better than the RB51 vaccine. Vaccination with znBAZ potently stimulated CD8⁺ T cells, whereas mucosal vaccination with RB51 induced mostly CD4⁺ T cells. Subsequent analysis revealed these pulmonary CD44⁺ CD69⁺ CD8⁺ T cells to be either CD103⁺ or CD103^- T_RM cells, and these sequestered to the lung parenchyma as CXCR3^lo and to the airways as CXCR3^hi. Both CD8⁺ T_RM subsets contained single-positive IFN-γ and TNF-α, as well as, polyfunctional cells. IL-17-producing CD8⁺ T_RM cells were also induced by znBAZ vaccination, but in vivo IL-17 neutralization had no impact upon protection. In vivo depletion of CD4⁺ T cells had no impact upon protection in znBAZ-vaccinated mice. In contrast, CD4⁺ T cell depletion reduced RB51’s protective efficacy in spleens and lungs by two- and three-logs, respectively. Although anti-CD8 mAb-treated znBAZ-vaccinated mice showed a significantly reduced pulmonary efficacy, this treatment failed to completely deplete the lung CD8⁺ T cells, leaving the CD103⁺ and CD103^- CD8⁺ T_RM cell ratios intact. Only znBAZ-vaccinated CD8^-/- mice were fully sensitive to pulmonary challenge with virulent wt B. abortus 2308 since CD8⁺ T_RM cells could not be induced. Collectively, these data demonstrate the key role of mucosal vaccination for the generation of CD8⁺ T_RM cells in protecting against pulmonary challenge with virulent B. abortus.

Klíčová slova:

Analysis of variance – Brucella – Cytotoxic T cells – Memory T cells – Spleen – T cells – Vaccination and immunization – Vaccines

Zdroje

1. Kerem E, Diav O, Navon P, Branski D. Pleural fluid characteristics in pulmonary brucellosis. Thorax. 1994 Jan;49(1):89–90. doi: 10.1136/thx.49.1.89 8153949

2. Byndloss MX, Tsolis RM. Brucella spp. Virulence factors and immunity. Annu Rev Anim Biosci. 2016;4: 111–127. doi: 10.1146/annurev-animal-021815-111326 26734887

3. Ko J, Splitter GA. Molecular host-pathogen interaction in brucellosis: current understanding and future approaches to vaccine development for mice and humans. Clin Microbiol Rev. 2003 Jan;16(1):65–78. doi: 10.1128/CMR.16.1.65-78.2003 12525425

4. de Figueiredo P, Ficht TA, Rice-Ficht A, Rossetti CA, Adams LG. Pathogenesis and immunobiology of brucellosis review of Brucella–host interactions. Am J Pathol. 2015 Jun;185(6):1505–17. doi: 10.1016/j.ajpath.2015.03.003 25892682

5. Challoner KR, Riley KB, Larsen RA. Brucella meningitis. Am J Emerg Med. 1990;8: 40–42. doi: 10.1016/0735-6757(90)90293-9 2293833

6. Demiraslan H, Metan G, Mese EA, Yildiz O, Aygen B, Sumerkan B, et al. Neurobrucellosis: an evaluation of a rare presentation of brucellosis from a tertiary care centre in Central Anatolia, Turkey. Trop Doct. 2009 Oct;39(4):233–5. doi: 10.1258/td.2009.080430 19762578

7. McDermott J, Grace D, Zinsstag J. Economics of brucellosis impact and control in low-income countries. Rev Sci Tech. 2013 Apr;32(1):249–61. doi: 10.20506/rst.32.1.2197 23837382

8. Golding B, Scott DE, Scharf O, Huang LY. Immunity and protection against Brucella abortus. Microbes Infect. 2001 Jan;3(1):43–8. doi: 10.1016/s1286-4579(00)01350-2 11226853

9. Svetić A, Jian YC, Lu P, Finkelman FD, Gause WC. Brucella abortus induces a novel cytokine gene expression pattern characterized by elevated IL-10 and IFN-gamma in CD4+ T cells. Int Immunol. 1993 Aug;5(8):877–83. doi: 10.1093/intimm/5.8.877 8104472

10. Fernandes DM, Jiang X, Jung JH, Baldwin CL. Comparison of T cell cytokines in resistant and susceptible mice infected with virulent Brucella abortus strain 2308. FEMS Immunol Med Microbiol. 1996 Dec 31;16(3–4):193–203. doi: 10.1111/j.1574-695X.1996.tb00136.x 9116636

11. Vitry MA, De Trez C, Goriely S, Dumoutier L, Akira S, Ryffel B, et al. Crucial role of gamma interferon-producing CD4+ Th1 cells but dispensable function of CD8+ T cell, B cell, Th2, and Th17 responses in the control of Brucella melitensis infection in mice. Infect Immun. 2012 Dec;80(12):4271–80. doi: 10.1128/IAI.00761-12 23006848

12. Vitry MA, Hanot Mambres D, De Trez C, Akira S, Ryffel B, Letesson JJ, et al. Humoral immunity and CD4+ Th1 cells are both necessary for a fully protective immune response upon secondary infection with Brucella melitensis. J Immunol. 2014 Apr 15;192(8):3740–52. doi: 10.4049/jimmunol.1302561 24646742

13. Oliveira SC, Harms JS, Banai M, Splitter GA. Recombinant Brucella abortus proteins that induce proliferation and gamma-interferon secretion by CD4+ T cells from Brucella-vaccinated mice and delayed-type hypersensitivity in sensitized guinea pigs. Cell Immunol. 1996 Sep 15;172(2):262–8. doi: 10.1006/cimm.1996.0241 8964089

14. Zhan Y, Kelso A, Cheers C. Differential activation of Brucella-reactive CD4+ T cells by Brucella infection or immunization with antigenic extracts. Infect Immun. 1995 Mar;63(3):969–75. 7868269

15. He Y, Vemulapalli R, Zeytun A, Schurig GG. Induction of specific cytotoxic lymphocytes in mice vaccinated with Brucella abortus RB51. Infect Immun. 2001 Sep;69(9):5502–8. doi: 10.1128/IAI.69.9.5502-5508.2001 11500423

16. Durward M, Radhakrishnan G, Harms J, Bareiss C, Magnani D, Splitter GA. Active evasion of CTL mediated killing and low quality responding CD8+ T cells contribute to persistence of brucellosis. PLoS One. 2012;7(4):e34925. doi: 10.1371/journal.pone.0034925 22558103

17. Cassataro J, Velikovsky CA, la Barrera de S, Estein SM, Bruno L, Bowden R, et al. A DNA vaccine coding for the Brucella outer membrane protein 31 confers protection against B. melitensis and B. ovis infection by eliciting a specific cytotoxic response. Infect Immun. 2005;73: 6537–6546. doi: 10.1128/IAI.73.10.6537-6546.2005 16177328

18. Dorneles EMS, de Faria APP, Pauletti RB, Santana JA, Caldeira GAV, Heinemann MB, et al. Genetic stability of Brucella abortus S19 and RB51 vaccine strains by multiple locus variable number tandem repeat analysis (MLVA16). Vaccine. 2013;31: 4856–4859. doi: 10.1016/j.vaccine.2013.07.063 23933375

19. Yang X, Clapp B, Thornburg T, Hoffman C, Pascual DW. Vaccination with a ΔnorD ΔznuA Brucella abortus mutant confers potent protection against virulent challenge. Vaccine. 2016;34: 5290–5297. doi: 10.1016/j.vaccine.2016.09.004 27639282

20. Durward-Diioia M, Harms J, Khan M, Hall C, Smith JA, Splitter GA. CD8+ T cell exhaustion, suppressed gamma interferon production, and delayed memory response induced by chronic Brucella melitensis infection. Infect Immun. 2015;83: 4759–4771. doi: 10.1128/IAI.01184-15 26416901

21. Hanot Mambres D, Machelart A, Potemberg G, De Trez C, Ryffel B, Letesson JJ, Muraille E. Identification of immune effectors essential to the control of primary and secondary intranasal infection with Brucella melitensis in mice. J Immunol. 2016 May 1;196(9):3780–93. doi: 10.4049/jimmunol.1502265 27036913

22. Clapp B, Yang X, Thornburg T, Walters N, Pascual DW. Nasal vaccination stimulates CD8+ T cells for potent protection against mucosal Brucella melitensis challenge. Immunol Cell Biol. 2016 May;94(5):496–508. doi: 10.1038/icb.2016.5 26752510

23. Clapp B, Skyberg JA, Yang X, Thornburg T, Walters N, Pascual DW. Protective live oral brucellosis vaccines stimulate Th1 and Th17 cell responses. Infect Immun. 2011 Oct;79(10):4165–74. doi: 10.1128/IAI.05080-11 21768283

24. Mackay IR, Rosen FS, von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med. 2000 Oct 5;343(14):1020–34. doi: 10.1056/NEJM200010053431407 11018170

25. Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401: 708–712. doi: 10.1038/44385 10537110

26. Beura LK, Masopust D. SnapShot: Resident memory T cells. Cell. 2014;157: 1488–1488. doi: 10.1016/j.cell.2014.05.026 24906159

27. Mueller SN, Mackay LK. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 2015;16: 79–89. doi: 10.1038/nri.2015.3 26688350

28. Lee WT, Pelletier WJ. Visualizing memory phenotype development after in vitro stimulation of CD4+ T cells. Cell. Immunol. 1998;188: 1–11. doi: 10.1006/cimm.1998.1341 9743552

29. Masopust D. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001 Mar 23;291(5512):2413–7. doi: 10.1126/science.1058867 11264538

30. Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T cell subsets, migration patterns, and tissue residence. Annu Rev. Immunol. 2013;31: 137–161. doi: 10.1146/annurev-immunol-032712-095954 23215646

31. Ariotti S, Haanen JB, Schumacher TN. Behavior and function of tissue-resident memory T cells. Adv Immunol. 2012;114:203–16. doi: 10.1016/B978-0-12-396548-6.00008-1 22449783

32. Bergsbaken T, Bevan MJ. Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection. Nat Immunol. 2015;16: 406–414. doi: 10.1038/ni.3108 25706747

33. Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature. 2012 Feb 29;483(7388):227–31. doi: 10.1038/nature10851 22388819

34. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon M-L, et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat Immunol. 2013;14: 1294–1301. doi: 10.1038/ni.2744 24162776

35. Schenkel JM, Fraser KA, Masopust D. Cutting Edge: Resident memory CD8 T cells occupy frontline niches in secondary lymphoid organs. J Immunol. 2014;192: 2961–2964. doi: 10.4049/jimmunol.1400003 24600038

36. Sheridan BS, Pham Q-M, Lee Y-T, Cauley LS, Puddington L, Lefrançois L. Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function. Immunity. 2014;40: 747–757. doi: 10.1016/j.immuni.2014.03.007 24792910

37. Shin H, Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature. 2012;491: 463–467. doi: 10.1038/nature11522 23075848

38. Takamura S, Yagi H, Hakata Y, Motozono C, McMaster SR, Masumoto T, et al. Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance. J Exp Med. 2016 Dec 12;213(13):3057–3073. doi: 10.1084/jem.20160938 27815325

39. Bevan MJ. Memory T cells as an occupying force. Eur J Immunol. 2011;41: 1192–1195. doi: 10.1002/eji.201041377 21469134

40. Schenkel JM, Fraser KA, Vezys V, Masopust D. Sensing and alarm function of resident memory CD8+ T cells. Nat Immunol. 2013;14: 509. doi: 10.1038/ni.2568 23542740

41. Mackay LK, Stock AT, Ma JZ. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci U S A. 2012 May 1;109(18):7037–42. doi: 10.1073/pnas.1202288109 22509047

42. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol. 2009;10: 524–530. doi: 10.1038/ni.1718 19305395

43. Anderson KG, Masopust D. Editorial: Pulmonary resident memory CD8 T cells: here today, gone tomorrow. J Leukoc Bio. 2014;95: 199–201. doi: 10.1189/jlb.0913493 24482485

44. Park CO, Kupper TS. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat Med. 2015;21: 688–697. doi: 10.1038/nm.3883 26121195

45. Anderson KG, Mayer-Barber K, Sung H, Beura L, James BR, Taylor JJ, et al. Intravascular staining for discrimination of vascular and tissue leukocytes. Nature Protocols. 2014;9: 209–222. doi: 10.1038/nprot.2014.005 24385150

46. Turner DL, Bickham KL, Thome JJ, Kim CY, D’Ovidio F, Wherry EJ, et al. Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol. 2013;7: 501–510. doi: 10.1038/mi.2013.67 24064670

47. Gilchuk P, Hill TM, Guy C, McMaster SR, Boyd KL, Rabacal WA, et al. A distinct lung-interstitium-resident memory CD8+ T cell aubset confers enhanced protection to lower respiratory tract infection. Cell Rep. 2016;16: 1800–1809. doi: 10.1016/j.celrep.2016.07.037 27498869

48. Laidlaw BJ, Zhang N, Marshall HD, Staron MM, Guan T, Hu Y, et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity. 2014 Oct 16;41(4):633–45. doi: 10.1016/j.immuni.2014.09.007 25308332

49. Stary G, Olive A, Radovic AF. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science. 2015 Jun 19;348(6241):aaa8205. doi: 10.1126/science.aaa8205 26089520

50. Sridhar S, Begom S, Bermingham A, Hoschler K, Adamson W, Carman W, et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med. 2013;19: 1305–1312. doi: 10.1038/nm.3350 24056771

51. Slütter B, Pewe LL, Kaech SM, Harty JT. Lung airway-surveilling CXCR3hi memory CD8+ T cells are critical for protection against influenza A virus. Immunity. 2013;39: 939–948. doi: 10.1016/j.immuni.2013.09.013 24238342

52. Hombrink P, Helbig C, Backer RA, Piet B, Oja AE, Stark R, et al. Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells. Nat Immunol. 2016;17: 1467–1478. doi: 10.1038/ni.3589 27776108

53. Wilkinson TM, Li CKF, Chui CSC, Huang AKY, Perkins M, Liebner JC, et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med. 2012;18: 274–280. doi: 10.1038/nm.2612 22286307

54. Wu T, Hu Y, Lee YT, Bouchard KR, Benechet A, Khanna K, et al. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J Leukoc Bio. 2014;95: 215–224. doi: 10.1189/jlb.0313180 24006506

55. Wakim LM, Gupta N, Mintern JD, Villadangos JA. Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3. Nat Immunol. 2013;14: 238–245. doi: 10.1038/ni.2525 23354485

56. McMaster SR, Wilson JJ, Wang H, Kohlmeier JE. Airway-resident memory CD8 T cells provide antigen-specific protection against respiratory virus challenge through rapid IFN-γ production. J Immunol. 2015;195: 203–209.

57. Lee YN, Lee YT, Kim MC, Gewirtz AT, Kang SM. A novel vaccination strategy mediating the induction of lung-resident memory CD8 T cells confers heterosubtypic immunity against future pandemic influenza virus. J Immunol. 2016 Mar 15;196(6):2637–45. doi: 10.4049/jimmunol.1501637 26864033

58. Perdomo C, Zedler U, Kühl AA, Lozza L, Saikali P, Sander LE, et al. Mucosal BCG vaccination induces protective lung-resident memory T cell populations against tuberculosis. MBio. 2016 Nov 22;7(6). doi: 10.1128/mBio.01686-16 27879332

59. Solans L, Debrie AS, Borkner L, Aguiló N, Thiriard A, Coutte L et al. IL-17-dependent SIgA-mediated protection against nasal Bordetella pertussis infection by live attenuated BPZE1 vaccine. Mucosal Immunol. 2018 Nov;11(6):1753–1762. doi: 10.1038/s41385-018-0073-9 30115992

60. Thawer SG, Horsnell WG, Darby M, Hoving JC, Dewals B, Cutler AJ, et al. Lung-resident CD4⁺ T cells are sufficient for IL-4Rα-dependent recall immunity to Nippostrongylus brasiliensis infection. Mucosal Immunol. 2014 Mar;7(2):239–48. doi: 10.1038/mi.2013.40 23778354

61. Hasenberg M, Stegemann-Koniszewski S, Gunzer M. Cellular immune reactions in the lung. Immunol Rev. 2013 Jan;251(1):189–214. doi: 10.1111/imr.12020 23278750

62. Anderson KG, Sung H, Skon CN, Lefrançois L, Deisinger A, Vezys V, et al. Cutting Edge: Intravascular staining redefines lung CD8 T cell responses. J Immunol. 2012;189: 2702–2706. doi: 10.4049/jimmunol.1201682 22896631

63. Pihlgren M, Arpin C, Walzer T, Tomkowiak M, Thomas A, Marvel J, et al. Memory CD44int CD8 T cells show increased proliferative responses and IFN-γ production following antigenic challenge in vitro. Int Immunol. 1999;11: 699–706. doi: 10.1093/intimm/11.5.699 10330275

64. Dhanji S, Teh SJ, Oble D, Priatel JJ, Teh HS. Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors. Blood. 2004;104: 2116–2123. doi: 10.1182/blood-2004-01-0150 15178577

65. Walzer T, Arpin C, Beloeil L, Marvel J. Differential in vivo persistence of two subsets of memory phenotype CD8 T cells defined by CD44 and CD122 expression levels. J Immunol. 2002;168: 2704–2711. doi: 10.4049/jimmunol.168.6.2704 11884436

66. Kohlmeier JE, Cookenham T, Miller SC, Roberts AD, Christensen JP, Thomsen AR, et al. CXCR3 directs antigen-specific effector CD4+ T cell migration to the lung during parainfluenza virus infection. J Immunol. 2009;183: 4378–4384. doi: 10.4049/jimmunol.0902022 19734208

67. Woodrow KA, Bennett KM, Lo DD. Mucosal vaccine design and delivery. Annu Rev Biomed Eng. 2012;14:17–46. doi: 10.1146/annurev-bioeng-071811-150054 22524387

68. Lycke N. Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol. 2012 Jul 25;12(8):592–605. doi: 10.1038/nri3251 22828912

69. Neutra MR, Kozlowski PA. Mucosal vaccines: the promise and the challenge. Nat revs Immunol. 2006;6: 148–158. doi: 10.1038/nri1777 16491139

70. Brandtzaeg P. Function of mucosa-associated lymphoid tissue in antibody formation. Immunol Invest. 2010;39: 303–355. doi: 10.3109/08820131003680369 20450282

71. Pasquali P, Rosanna A, Pistoia C, Petrucci P, Ciuchini F. Brucella abortus RB51 induces protection in mice orally infected with the virulent strain B. abortus 2308. Infect Immun. 2003 May;71(5):2326–30. doi: 10.1128/IAI.71.5.2326-2330.2003 12704101

72. Baldwin CL, Goenka R. Host immune responses to the intracellular bacteria Brucella: does the bacteria instruct the host to facilitate chronic infection? Crit Rev Immunol. 2006;26(5):407–42. doi: 10.1615/critrevimmunol.v26.i5.30 17341186

73. Andrews E, Salgado P, Folch H, Onate A. Vaccination with live Escherichia coli expressing Brucella abortus Cu/Zn superoxide-dismutase: II. Induction of specific CD8+ cytotoxic lymphocytes and sensitized CD4+ IFN-γ-producing cell. Microbiol Immunol. 2006;50(5):389–93. doi: 10.1111/j.1348-0421.2006.tb03805.x 16714846

74. Yingst SL, Izadjoo M, Hoover DL. CD8 knockout mice are protected from challenge by vaccination with WR201, a live attenuated mutant of Brucella melitensis. Clin Dev Immunol. 2013;2013:686919. doi: 10.1155/2013/686919 24288554

75. Kelchtermans H, Schurgers E, Geboes L, Mitera T, Van Damme J, Van Snick J, et al. Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon-γ and counteraction by interferon-γ. Arthritis Res Ther. 2009;11(4):R122. doi: 10.1186/ar2787 19686583

76. Guo S, Cobb D, Smeltz RB. T-bet inhibits the in vivo differentiation of parasite-specific CD4+ Th17 cells in a T cell-intrinsic manner. J Immunol. 2009 May 15;182(10):6179–86. doi: 10.4049/jimmunol.0803821 19414771

77. Dar HY, Shukla P, Mishra PK, Anupam R, Mondal RK, Tomar GB, et al. Lactobacillus acidophilus inhibits bone loss and increases bone heterogeneity in osteoporotic mice via modulating Treg-Th17 cell balance. Bone Rep. 2018 Feb 5;8:46–56. doi: 10.1016/j.bonr.2018.02.001 29955622

78. Masopust D, Picker LJ. Hidden memories: frontline memory T cells and early pathogen interception. J Immunol. 2012 Jun 15;188(12):5811–7. doi: 10.4049/jimmunol.1102695 22675215

79. Clark RA. Resident memory T cells in human health and disease. Sci Transl Med. 2015 Jan 7;7(269):269rv1. doi: 10.1126/scitranslmed.3010641 25568072

80. Schenkel JM, Fraser KA, Beura LK, Pauken KE, Vezys V, Masopust D. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science. 2014 Oct 3;346(6205):98–101. doi: 10.1126/science.1254536 25170049

81. Shiow LR, Rosen DB, Brdicková N, Xu Y, An J, Lanier LL, et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature. 2006;440: 540–544. doi: 10.1038/nature04606 16525420

82. Sancho D, Gómez M, Sánchez-Madrid F. CD69 is an immunoregulatory molecule induced following activation. Trends Immunol. 2005 Mar;26(3):136–40. doi: 10.1016/j.it.2004.12.006 15745855

83. Turner DL, Farber DL. Mucosal resident memory CD4 T cells in protection and immunopathology. Front Immunol. 2014 Jul 14;5:331. doi: 10.3389/fimmu.2014.00331 25071787

84. Casey KA, Fraser KA, Schenkel JM, Moran A, Abt MC, Beura LK, et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J Immunol. 2012;188: 4866–4875. doi: 10.4049/jimmunol.1200402 22504644

85. Mackay LK, Braun A, Macleod BL, Collins N, Tebartz C, Bedoui S, et al. Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention. J Immunol. 2015 Mar 1;194(5):2059–63. doi: 10.4049/jimmunol.1402256 25624457

86. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell. 1994;76: 301–314. doi: 10.1016/0092-8674(94)90337-9 7507411

87. Förster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Revs Immunol. 2008;8: 362–371. doi: 10.1038/nri2297 18379575

88. Bromley SK, Thomas SY, Luster AD. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol. 2005;6: 895. doi: 10.1038/ni1240 16116469

89. Bromley SK, Yan S, Tomura M, Kanagawa O, Luster AD. Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J Immunol. 2012;190: 970–976. doi: 10.4049/jimmunol.1202805 23255361

90. Watanabe R, Gehad A, Yang C, Scott LL, Teague JE, Schlapbach C, et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Transl Med. 2015 Mar 18;7(279):279ra39. doi: 10.1126/scitranslmed.3010302 25787765

91. Perdomo C, Zedler U, Kühl AA, Lozza L, Saikali P, Sander LE, et al. Mucosal BCG vaccination induces protective lung-resident memory T cell populations against tuberculosis. MBio. 2016 Nov 22;7(6). pii: e01686–16. doi: 10.1128/mBio.01686-16 27879332

92. Obar JJ, Lefrançois L. Memory CD8+ T cell differentiation. Ann N Y Acad Sci. 2010 Jan;1183:251–66. doi: 10.1111/j.1749-6632.2009.05126.x 20146720

93. Sarkar S, Kalia V, Haining WN, Konieczny BT, Subramaniam S, Ahmed R. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J Exp Med. 2008 Mar 17;205(3):625–40. doi: 10.1084/jem.20071641 18316415

94. Masopust D, Ha SJ, Vezys V, Ahmed R. Stimulation history dictates memory CD8 T cell phenotype: implications for prime-boost vaccination. J Immunol. 2006;177: 831–839. doi: 10.4049/jimmunol.177.2.831 16818737

95. Mackay LK, Carbone FR. CD4 helpers put tissue-resident memory cells in their place. Immunity. 2014;41: 514–515. doi: 10.1016/j.immuni.2014.09.018 25367567