Development and function of protective and pathologic memory CD4 T cells

Frontiers in Immunology

Volumn 6, Issue SEP, 2015, Pages

  Jaigirdar, Shafqat Ahrar ^a   MacLeod, Megan K L ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

Autoimmunity; CD4 T cell; Cytokine; Differentiation; Epigenetic; Infection; Memory; Vaccine

Indexed keywords

CD28 ANTIGEN; CD45RO ANTIGEN; CD69 ANTIGEN; CHEMOKINE RECEPTOR CCR7; CHEMOKINE RECEPTOR CXCR3; CHEMOKINE RECEPTOR CXCR5; FAS ANTIGEN; GAMMA INTERFERON; INTERLEUKIN 4; INTERLEUKIN 7 RECEPTOR; L SELECTIN; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2;

ANTIGEN PRESENTATION; AUTOIMMUNE DISEASE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL MIGRATION; CELL PROLIFERATION; CENTRAL MEMORY; DOWN REGULATION; EFFECTOR MEMORY; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL MEMORY; IMMUNOPATHOLOGY; MEMORY T LYMPHOCYTE; NONHUMAN; RESIDENT MEMORY; REVIEW; T LYMPHOCYTE ACTIVATION;

EID: 84946547805     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2015.00456     Document Type: Review

References (138)

1. Hinman AR, Orenstein WA, Schuchat A. Vaccine-preventable diseases, immunizations, and MMWR-1961-2011. 7 ed. Morbidity and Mortality Weekly Report (MMWR). (2011). Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/su6004a9.htm.
2. Sprent J, Cho JH, Boyman O, Surh CD. T cell homeostasis. Immunol Cell Biol (2008) 86:312-9. doi: 10.1038/icb.2008.12.
3. Plotkin SA. Vaccines: correlates of vaccine-induced immunity. Clin Infect Dis (2008) 47:401-9. doi:10.1086/589862.
4. Harty JT, Tvinnereim AR, White DW. CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol (2000) 18:275-308. doi:10.1146/annurev.immunol.18.1.275.
5. Vasconcelos JR, Dominguez MR, Araujo AF, Ersching J, Tararam CA, Bruna-Romero O, et al. Relevance of long-lived CD8(+) T effector memory cells for protective immunity elicited by heterologous prime-boost vaccination. Front Immunol (2012) 3:358. doi:10.3389/fimmu.2012.00358.
6. Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med (1987) 165:302-19. doi:10.1084/jem.165.2.302.
7. Kearney ER, Pape KA, Loh DY, Jenkins MK. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity (1994) 1:327-39. doi:10.1016/1074-7613(94)90084-1.
8. Stary G, Olive A, Radovic-Moreno AF, Gondek D, Alvarez D, Basto PA, et al. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science (2015) 348:aaa8205. doi:10.1126/science.aaa8205.
9. Schmitt N, Ueno H. Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol (2015) 34:130-6. doi:10.1016/j.coi.2015.03.007.
10. O'Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science (2010) 327:1098-102. doi:10.1126/science.1178334.
11. Joshi NS, Kaech SM. Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J Immunol (2008) 180:1309-15. doi:10.4049/jimmunol.180.3.1309.
12. Seder RA, Darrah PA, Roederer M. T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol (2008) 8:247-58. doi:10.1038/nri2274.
13. Opata MM, Stephens R. Early decision: effector and effector memory T cell differentiation in chronic infection. Curr Immunol Rev (2013) 9:190-206. doi:10.2174/1573395509666131126231209.
14. Harrington LE, Janowski KM, Oliver JR, Zajac AJ, Weaver CT. Memory CD4 T cells emerge from effector T-cell progenitors. Nature (2008) 452:356-60. doi:10.1038/nature06672.
15. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature (1999) 401:708-12. doi:10.1038/44385.
16. Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nat Immunol (2011) 12:467-71. doi:10.1038/ni.2038.
17. Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T cell subsets, migration patterns, and tissue residence. Annu Rev Immunol (2013) 31:137-61. doi:10.1146/annurev-immunol-032712-095954.
18. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A human memory T cell subset with stem cell-like properties. Nat Med (2011) 17:1290-7. doi:10.1038/nm.2446.
19. Luckey CJ, Weaver CT. Stem-cell-like qualities of immune memory; CD4+ T cells join the party. Cell Stem Cell (2012) 10:107-8. doi:10.1016/j.stem.2012.01.011.
20. Biasco L, Scala S, Basso Ricci L, Dionisio F, Baricordi C, Calabria A, et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci Transl Med (2015) 7:273ra213. doi:10.1126/scitranslmed.3010314.
21. Fuertes Marraco SA, Soneson C, Cagnon L, Gannon PO, Allard M, Abed Maillard S, et al. Long-lasting stem cell-like memory CD8+ T cells with a naive-like profile upon yellow fever vaccination. Sci Transl Med (2015) 7:282ra248. doi:10.1126/scitranslmed.aaa3700.
22. Schmueck-Henneresse M, Sharaf R, Vogt K, Weist BJ, Landwehr-Kenzel S, Fuehrer H, et al. Peripheral blood-derived virus-specific memory stem T cells mature to functional effector memory subsets with self-renewal potency. J Immunol (2015) 194:5559-67. doi:10.4049/jimmunol.1402090.
23. Takeshita M, Suzuki K, Kassai Y, Takiguchi M, Nakayama Y, Otomo Y, et al. Polarization diversity of human CD4 stem cell memory T cells. Clin Immunol (2015) 159:107-17. doi:10.1016/j.clim.2015.04.010.
24. Fazilleau N, Eisenbraun MD, Malherbe L, Ebright JN, Pogue-Caley RR, Mcheyzer-Williams LJ, et al. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat Immunol (2007) 8:753-61. doi:10.1038/ni1472.
25. MacLeod MK, David A, Mckee AS, Crawford F, Kappler JW, Marrack P. Memory CD4 T cells that express CXCR5 provide accelerated help to B cells. J Immunol (2011) 186:2889-96. doi:10.4049/jimmunol.1002955.
26. Lugli E, Dominguez MH, Gattinoni L, Chattopadhyay PK, Bolton DL, Song K, et al. Superior T memory stem cell persistence supports long-lived T cell memory. J Clin Invest (2013) 123:594-9. doi:10.1172/JCI66327.
27. Suan D, Nguyen A, Moran I, Bourne K, Hermes JR, Arshi M, et al. T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses. Immunity (2015) 42:704-18. doi:10.1016/j.immuni.2015.03.002.
28. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med (2005) 11:1299-305. doi:10.1038/nm1326.
29. Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med (2009) 15:808-13. doi:10.1038/nm.1982.
30. Muranski P, Borman ZA, Kerkar SP, KlebanoffCA, Ji Y, Sanchez-Perez L, et al. Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity (2011) 35:972-85. doi:10.1016/j.immuni.2011.09.019.
31. Schenkel JM, Masopust D. Tissue-resident memory T cells. Immunity (2014) 41:886-97. doi:10.1016/j.immuni.2014.12.007.
32. Zens KD, Farber DL. Memory CD4 T cells in influenza. Curr Top Microbiol Immunol (2015) 386:399-421. doi:10.1007/82_2014_401.
33. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, et al. The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. Nat Immunol (2013) 14:1294-301. doi:10.1038/ni.2744.
34. Steinert EM, Schenkel JM, Fraser KA, Beura LK, Manlove LS, Igyarto BZ, et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell (2015) 161:737-49. doi:10.1016/j.cell.2015.03.031.
35. Ledgerwood LG, Lal G, Zhang N, Garin A, Esses SJ, Ginhoux F, et al. The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nat Immunol (2008) 9:42-53. doi:10.1038/ni1534.
36. Lee YT, Suarez-Ramirez JE, Wu T, Redman JM, Bouchard K, Hadley GA, et al. Environmental and antigen receptor-derived signals support sustained surveillance of the lungs by pathogen-specific cytotoxic T lymphocytes. J Virol (2011) 85:4085-94. doi:10.1128/JVI.02493-10.
37. 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) 188:4866-75. doi:10.4049/jimmunol.1200402.
38. Zhang N, Bevan MJ. Transforming growth factor-beta signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity (2013) 39:687-96. doi:10.1016/j.immuni.2013.08.019.
39. Teijaro JR, Turner D, Pham Q, Wherry EJ, Lefrancois L, Farber DL. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol (2011) 187:5510-4. doi:10.4049/jimmunol.1102243.
40. Thome JJ, Yudanin N, Ohmura Y, Kubota M, Grinshpun B, Sathaliyawala T, et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell (2014) 159:814-28. doi:10.1016/j.cell.2014.10.026.
41. 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) 7:279ra239. doi:10.1126/scitranslmed.3010302.
42. Clark RA, Watanabe R, Teague JE, Schlapbach C, Tawa MC, Adams N, et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci Transl Med (2012) 4:117ra117. doi:10.1126/scitranslmed.3003008.
43. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature (2011) 477:216-9. doi:10.1038/nature10339.
44. Davila SJ, Olive AJ, Starnbach MN. Integrin alpha4beta1 is necessary for CD4+ T cell-mediated protection against genital Chlamydia trachomatis infection. J Immunol (2014) 192:4284-93. doi:10.4049/jimmunol.1303238.
45. Strutt TM, Mckinstry KK, Dibble JP, Winchell C, Kuang Y, Curtis JD, et al. Memory CD4+ T cells induce innate responses independently of pathogen. Nat Med (2010) 16:558-64. doi:10.1038/nm.2142.
46. Nakanishi Y, Lu B, Gerard C, Iwasaki A. CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature (2009) 462:510-3. doi:10.1038/nature08511.
47. Sakai S, Kauffman KD, Schenkel JM, Mcberry CC, Mayer-Barber KD, Masopust D, et al. Cutting edge: control of Mycobacterium tuberculosis infection by a subset of lung parenchyma-homing CD4 T cells. J Immunol (2014) 192:2965-9. doi:10.4049/jimmunol.1400019.
48. Moguche AO, Shafiani S, Clemons C, Larson RP, Dinh C, Higdon LE, et al. ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis. J Exp Med (2015) 212:715-28. doi:10.1084/jem.20141518.
49. Peters NC, Pagan AJ, Lawyer PG, Hand TW, Henrique Roma E, Stamper LW, et al. Chronic parasitic infection maintains high frequencies of short-lived Ly6C+CD4+ effector T cells that are required for protection against re-infection. PLoS Pathog (2014) 10:e1004538. doi:10.1371/journal.ppat.1004538.
50. Zaph C, Rook KA, Goldschmidt M, Mohrs M, Scott P, Artis D. Persistence and function of central and effector memory CD4+ T cells following infection with a gastrointestinal helminth. J Immunol (2006) 177:511-8. doi:10.4049/jimmunol.177.1.511.
51. Else KJ, Finkelman FD, Maliszewski CR, Grencis RK. Cytokine-mediated regulation of chronic intestinal helminth infection. J Exp Med (1994) 179:347-51. doi:10.1084/jem.179.1.347.
52. Bending D, De La Pena H, Veldhoen M, Phillips JM, Uyttenhove C, Stockinger B, et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest (2009) 119:565-72. doi:10.1172/JCI37865.
53. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, et al. Late developmental plasticity in the T helper 17 lineage. Immunity (2009) 30:92-107. doi:10.1016/j.immuni.2008.11.005.
54. Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol (2011) 12:255-63. doi:10.1038/ni.1993.
55. McGeachy MJ. Th17 memory cells: live long and proliferate. J Leukoc Biol (2013) 94:921-6. doi:10.1189/jlb.0313113.
56. Pepper M, Linehan JL, Pagan AJ, Zell T, Dileepan T, Cleary PP, et al. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat Immunol (2010) 11:83-9. doi:10.1038/ni.1826.
57. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol (2011) 29:621-63. doi:10.1146/annurev-immunol-031210-101400.
58. He J, Tsai LM, Leong YA, Hu X, Ma CS, Chevalier N, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity (2013) 39:770-81. doi:10.1016/j.immuni.2013.09.007.
59. Brown DM, Dilzer AM, Meents DL, Swain SL. CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol (2006) 177:2888-98. doi:10.4049/jimmunol.177.5.2888.
60. Alexander J, Bilsel P, Del Guercio MF, Stewart S, Marinkovic-Petrovic A, Southwood S, et al. Universal influenza DNA vaccine encoding conserved CD4+ T cell epitopes protects against lethal viral challenge in HLA-DR transgenic mice. Vaccine (2010) 28:664-72. doi:10.1016/j.vaccine.2009.10.103.
61. Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet (2013) 381:1021-8. doi:10.1016/S0140-6736(13)60177-4.
62. Tameris M, Geldenhuys H, Luabeya AK, Smit E, Hughes JE, Vermaak S, et al. The candidate TB vaccine, MVA85A, induces highly durable Th1 responses. PLoS One (2014) 9:e87340. doi:10.1371/journal.pone.0087340.
63. Liang S, Mozdzanowska K, Palladino G, Gerhard W. Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity. J Immunol (1994) 152:1653-61.
64. Obst R, Van Santen HM, Melamed R, Kamphorst AO, Benoist C, Mathis D. Sustained antigen presentation can promote an immunogenic T cell response, like dendritic cell activation. Proc Natl Acad Sci U S A (2007) 104:15460-5. doi:10.1073/pnas.0707331104.
65. Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, et al. Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection. Immunity (2011) 35:633-46. doi:10.1016/j.immuni.2011.08.016.
66. Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, et al. Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection. Immunity (2014) 40:289-302. doi:10.1016/j.immuni.2014.01.005.
67. Kahan SM, Wherry EJ, Zajac AJ. T cell exhaustion during persistent viral infections. Virology (2015) 479-480C:180-93. doi:10.1016/j.virol.2014.12.033.
68. Baumgartner CK, Yagita H, Malherbe LP. A TCR affinity threshold regulates memory CD4 T cell differentiation following vaccination. J Immunol (2012) 189:2309-17. doi:10.4049/jimmunol.1200453.
69. Gett AV, Sallusto F, Lanzavecchia A, Geginat J. T cell fitness determined by signal strength. Nat Immunol (2003) 4:355-60. doi:10.1038/ni908.
70. Williams MA, Ravkov EV, Bevan MJ. Rapid culling of the CD4+ T cell repertoire in the transition from effector to memory. Immunity (2008) 28:533-45. doi:10.1016/j.immuni.2008.02.014.
71. Kim EH, Sullivan JA, Plisch EH, Tejera MM, Jatzek A, Choi KY, et al. Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J Immunol (2012) 188:4305-14. doi:10.4049/jimmunol.1103568.
72. Tubo NJ, Pagan AJ, Taylor JJ, Nelson RW, Linehan JL, Ertelt JM, et al. Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell (2013) 153:785-96. doi:10.1016/j.cell.2013.04.007.
73. Becattini S, Latorre D, Mele F, Foglierini M, De Gregorio C, Cassotta A, et al. T cell immunity. Functional heterogeneity of human memory CD4(+) T cell clones primed by pathogens or vaccines. Science (2015) 347:400-6. doi:10.1126/science.1260668.
74. Gaide O, Emerson RO, Jiang X, Gulati N, Nizza S, Desmarais C, et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat Med (2015) 21:647-53. doi:10.1038/nm.3860.
75. Buchholz VR, Flossdorf M, Hensel I, Kretschmer L, Weissbrich B, Graf P, et al. Disparate individual fates compose robust CD8+ T cell immunity. Science (2013) 340:630-5. doi:10.1126/science.1235454.
76. Gerlach C, Rohr JC, Perie L, Van Rooij N, Van Heijst JW, Velds A, et al. Heterogeneous differentiation patterns of individual CD8+ T cells. Science (2013) 340:635-9. doi:10.1126/science.1235487.
77. Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol (2003) 3:269-79. doi:10.1038/nri1052.
78. Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol (2003) 4:1191-8. doi:10.1038/ni1009.
79. Sun JC, Lehar SM, Bevan MJ. Augmented IL-7 signaling during viral infection drives greater expansion of effector T cells but does not enhance memory. J Immunol (2006) 177:4458-63. doi:10.4049/jimmunol.177.7.4458.
80. Tripathi P, Mitchell TC, Finkelman F, Hildeman DA. Cutting edge: limiting amounts of IL-7 do not control contraction of CD4+ T cell responses. J Immunol (2007) 178:4027-31. doi:10.4049/jimmunol.178.7.4027.
81. Haring JS, Jing X, Bollenbacher-Reilley J, Xue HH, Leonard WJ, Harty JT. Constitutive expression of IL-7 receptor alpha does not support increased expansion or prevent contraction of antigen-specific CD4 or CD8 T cells following Listeria monocytogenes infection. J Immunol (2008) 180:2855-62. doi:10.4049/jimmunol.180.5.2855.
82. McKinstry KK, Strutt TM, Bautista B, Zhang W, Kuang Y, Cooper AM, et al. Effector CD4 T-cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nat Commun (2014) 5:5377. doi:10.1038/ncomms6377.
83. Catron DM, Rusch LK, Hataye J, Itano AA, Jenkins MK. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells. J Exp Med (2006) 203:1045-54. doi:10.1084/jem.20051954.
84. Linton PJ, Harbertson J, Bradley LM. A critical role for B cells in the development of memory CD4 cells. J Immunol (2000) 165:5558-65. doi:10.4049/jimmunol.165.10.5558.
85. van Essen D, Dullforce P, Brocker T, Gray D. Cellular interactions involved in Th cell memory. J Immunol (2000) 165:3640-6. doi:10.4049/jimmunol.165.7.3640.
86. Liu Q, Liu Z, Rozo CT, Hamed HA, Alem F, Urban JF Jr, et al. The role of B cells in the development of CD4 effector T cells during a polarized Th2 immune response. J Immunol (2007) 179:3821-30. doi:10.4049/jimmunol.179.6.3821.
87. Whitmire JK, Asano MS, Kaech SM, Sarkar S, Hannum LG, Shlomchik MJ, et al. Requirement of B cells for generating CD4+ T cell memory. J Immunol (2009) 182:1868-76. doi:10.4049/jimmunol.0802501.
88. Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ, Jenkins MK. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity (2011) 35:583-95. doi:10.1016/j.immuni.2011.09.009.
89. Crawford A, Macleod M, Schumacher T, Corlett L, Gray D. Primary T cell expansion and differentiation in vivo requires antigen presentation by B cells. J Immunol (2006) 176:3498-506. doi:10.4049/jimmunol.176.6.3498.
90. Barr TA, Brown S, Mastroeni P, Gray D. TLR and B cell receptor signals to B cells differentially program primary and memory Th1 responses to Salmonella enterica. J Immunol (2010) 185:2783-9. doi:10.4049/jimmunol.1001431.
91. Choi YS, Yang JA, Yusuf I, Johnston RJ, Greenbaum J, Peters B, et al. Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. J Immunol (2013) 190:4014-26. doi:10.4049/jimmunol.1202963.
92. Hale JS, Youngblood B, Latner DR, Mohammed AU, Ye L, Akondy RS, et al. Distinct memory CD4+ T cells with commitment to T follicular helper-and T helper 1-cell lineages are generated after acute viral infection. Immunity (2013) 38:805-17. doi:10.1016/j.immuni.2013.02.020.
93. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity (2008) 29:138-49. doi:10.1016/j.immuni.2008.05.009.
94. Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, Weinstein JS, et al. In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol (2010) 185:313-26. doi:10.4049/jimmunol.0904023.
95. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature (2003) 424:88-93. doi:10.1038/nature01726.
96. McCully ML, Collins PJ, Hughes TR, Thomas CP, Billen J, O'donnell VB, et al. Skin metabolites define a new paradigm in the localization of skin tropic memory T Cells. J Immunol (2015) 195. doi:10.4049/jimmunol.1402961.
97. Chandok MR, Okoye FI, Ndejembi MP, Farber DL. A biochemical signature for rapid recall of memory CD4 T cells. J Immunol (2007) 179:3689-98. doi:10.4049/jimmunol.179.6.3689.
98. Adachi K, Davis MM. T-cell receptor ligation induces distinct signaling pathways in naive vs. antigen-experienced T cells. Proc Natl Acad Sci U S A (2011) 108:1549-54. doi:10.1073/pnas.1017340108.
99. Kumar R, Ferez M, Swamy M, Arechaga I, Rejas MT, Valpuesta JM, et al. Increased sensitivity of antigen-experienced T cells through the enrichment of oligomeric T cell receptor complexes. Immunity (2011) 35:375-87. doi:10.1016/j.immuni.2011.08.010.
100. von Essen MR, Kongsbak M, Geisler C. Mechanisms behind functional avidity maturation in T cells. Clin Dev Immunol (2012) 2012:163453. doi:10.1155/2012/163453.
101. Weng NP, Araki Y, Subedi K. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol (2012) 12:306-15. doi:10.1038/nri3173.
102. Zimmermann C, Prevost-Blondel A, Blaser C, Pircher H. Kinetics of the response of naive and memory CD8 T cells to antigen: similarities and differences. Eur J Immunol (1999) 29:284-90. doi:10.1002/(SICI)1521-4141(199901)29:01 < 284::AID-IMMU284 > 3.0.CO;2-C.
103. Rogers PR, Dubey C, Swain SL. Qualitative changes accompany memory T cell generation: faster, more effective responses at lower doses of antigen. J Immunol (2000) 164:2338-46. doi:10.4049/jimmunol.164.5.2338.
104. Veiga-Fernandes H, Walter U, Bourgeois C, Mclean A, Rocha B. Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nat Immunol (2000) 1:47-53. doi:10.1038/76907.
105. Whitmire JK, Eam B, Whitton JL. Tentative T cells: memory cells are quick to respond, but slow to divide. PLoS Pathog (2008) 4:e1000041. doi:10.1371/journal.ppat.1000041.
106. Mehlhop-Williams ER, Bevan MJ. Memory CD8 + T cells exhibit increased antigen threshold requirements for recall proliferation. J Exp Med (2014) 211:345-56. doi:10.1084/jem.20131271.
107. Busch DH, Pamer EG. T cell affinity maturation by selective expansion during infection. J Exp Med (1999) 189:701-10. doi:10.1084/jem.189.4.701.
108. Slifka MK, Whitton JL. Functional avidity maturation of CD8(+) T cells without selection of higher affinity TCR. Nat Immunol (2001) 2:711-7. doi:10.1038/90650.
109. Turula H, Smith CJ, Grey F, Zurbach KA, Snyder CM. Competition between T cells maintains clonal dominance during memory inflation induced by MCMV. Eur J Immunol (2013) 43:1252-63. doi:10.1002/eji.201242940.
110. Ericsson PO, Orchansky PL, Carlow DA, Teh HS. Differential activation of phospholipase C-gamma 1 and mitogen-activated protein kinase in naive and antigen-primed CD4 T cells by the peptide/MHC ligand. J Immunol (1996) 156:2045-53.
111. Rogers PR, Croft M. CD28, Ox-40, LFA-1, and CD4 modulation of Th1/Th2 differentiation is directly dependent on the dose of antigen. J Immunol (2000) 164:2955-63. doi:10.4049/jimmunol.164.6.2955.
112. Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science (2010) 330:612-6. doi:10.1126/science.1191078.
113. Komori HK, Hart T, Lamere SA, Chew PV, Salomon DR. Defining CD4 T cell memory by the epigenetic landscape of CpG DNA methylation. J Immunol (2015) 194:1565-79. doi:10.4049/jimmunol.1401162.
114. Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, et al. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol (2007) 8:732-42. doi:10.1038/ni1474.
115. Dong J, Chang HD, Ivascu C, Qian Y, Rezai S, Okhrimenko A, et al. Loss of methylation at the IFNG promoter and CNS-1 is associated with the development of functional IFN-gamma memory in human CD4(+) T lymphocytes. Eur J Immunol (2013) 43:793-804. doi:10.1002/eji.201242858.
116. Agarwal S, Avni O, Rao A. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity (2000) 12:643-52. doi:10.1016/S1074-7613(00)80215-0.
117. Lee DU, Agarwal S, Rao A. Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity (2002) 16:649-60. doi:10.1016/S1074-7613(02)00314-X.
118. Tykocinski LO, Hajkova P, Chang HD, Stamm T, Sozeri O, Lohning M, et al. A critical control element for interleukin-4 memory expression in T helper lymphocytes. J Biol Chem (2005) 280:28177-85. doi:10.1074/jbc. M502038200.
119. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol (2002) 3:643-51. doi:10.1038/ni808.
120. Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes. Nat Immunol (2003) 4:78-86. doi:10.1038/ni872.
121. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4 + T cells. Immunity (2009) 30:155-67. doi:10.1016/j.immuni.2008.12.009.
122. Teijaro JR, Njau MN, Verhoeven D, Chandran S, Nadler SG, Hasday J, et al. Costimulation modulation uncouples protection from immunopathology in memory T cell responses to influenza virus. J Immunol (2009) 182:6834-43. doi:10.4049/jimmunol.0803860.
123. Penaloza-MacMaster P, Barber DL, Wherry EJ, Provine NM, Teigler JE, Parenteau L, et al. Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection. Science (2015) 347:278-82. doi:10.1126/science.aaa2148.
124. Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM, Tumpey TM. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog (2008) 4:e1000115. doi:10.1371/journal.ppat.1000115.
125. Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature (2012) 484:519-23. doi:10.1038/nature10921.
126. Paquette SG, Banner D, Chi Le TB, Leomicronn AJ, Xu L, Ran L, et al. Pandemic H1N1 influenza A directly induces a robust and acute inflammatory gene signature in primary human bronchial epithelial cells downstream of membrane fusion. Virology (2014) 448:91-103. doi:10.1016/j.virol.2013.09.022.
127. Law SC, Street S, Yu CH, Capini C, Ramnoruth S, Nel HJ, et al. T-cell autoreactivity to citrullinated autoantigenic peptides in rheumatoid arthritis patients carrying HLA-DRB1 shared epitope alleles. Arthritis Res Ther (2012) 14:R118. doi:10.1186/ar3848.
128. James EA, Rieck M, Pieper J, Gebe JA, Yue BB, Tatum M, et al. Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol (2014) 66:1712-22. doi:10.1002/art.38637.
129. Cao Y, Goods BA, Raddassi K, Nepom GT, Kwok WW, Love JC, et al. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci Transl Med (2015) 7:287ra274. doi:10.1126/scitranslmed.aaa8038.
130. Wambre E, Delong JH, James EA, Torres-Chinn N, Pfutzner W, Mobs C, et al. Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J Allergy Clin Immunol (2014) 133(872-879):e877. doi:10.1016/j.jaci.2013.10.054.
131. Zaleska A, Eiwegger T, Soyer O, Van De Veen W, Rhyner C, Soyka MB, et al. Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine. Allergy (2014) 69:1162-70. doi:10.1111/all.12461.
132. MacLeod MK, Anderton SM. Antigen-based immunotherapy (AIT) for autoimmune and allergic disease. Curr Opin Pharmacol (2015) 23:11-6. doi:10.1016/j.coph.2015.05.003.
133. Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev (2011) 241:180-205. doi:10.1111/j.1600-065X.2011.01011.x.
134. MacLeod M, Kwakkenbos MJ, Crawford A, Brown S, Stockinger B, Schepers K, et al. CD4 memory T cells survive and proliferate but fail to differentiate in the absence of CD40. J Exp Med (2006) 203:897-906. doi:10.1084/jem.20050711.
135. Ndlovu H, Darby M, Froelich M, Horsnell W, Luhder F, Hunig T, et al. Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4(+) T cell responses. PLoS Pathog (2014) 10:e1003906. doi:10.1371/journal.ppat.1003906.
136. David A, Crawford F, Garside P, Kappler JW, Marrack P, Macleod M. Tolerance induction in memory CD4 T cells requires two rounds of antigen-specific activation. Proc Natl Acad Sci U S A (2014) 111:7735-40. doi:10.1073/pnas.1406218111.
137. Mackenzie KJ, Nowakowska DJ, Leech MD, Mcfarlane AJ, Wilson C, Fitch PM, et al. Effector and central memory T helper 2 cells respond differently to peptide immunotherapy. Proc Natl Acad Sci U S A (2014) 111:E784-93. doi:10.1073/pnas.1316178111.
138. McPherson RC, Konkel JE, Prendergast CT, Thomson JP, Ottaviano R, Leech MD, et al. Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy. eLife (2014) 3:e03416. doi:10.7554/eLife.0341.