Flow-cytometric analysis of rare antigen-specific T cells

Cytometry Part A

Volumn 83, Issue 8, 2013, Pages 692-701

  Bacher, Petra ^a   Scheffold, Alexander ^b  

^a MILTENYI BIOTEC GMBH   (Germany)

^b CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

Antigen specific T cells; CD137; CD154; Cytokine secretion assay; Flow cytometry; MACS; MHC multimer; Rare cells; Tetramer

Indexed keywords

LEUKOCYTE ANTIGEN; LYMPHOCYTE ANTIGEN RECEPTOR; TETRAMER;

ANIMAL; ANTIGEN-SPECIFIC T CELLS; CD137; CD154; CELL SEPARATION; CYTOKINE SECRETION ASSAY; CYTOLOGY; FLOW CYTOMETRY; FLOW-CYTOMETRY; HUMAN; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; MACS; METABOLISM; METHODOLOGY; MHC MULTIMER; RARE CELLS; REGULATORY T LYMPHOCYTE; REVIEW; PROCEDURES;

ANTIGEN-SPECIFIC T CELLS; CD137; CD154; CYTOKINE SECRETION ASSAY; FLOW-CYTOMETRY; MACS; MHC MULTIMER; RARE CELLS; TETRAMER;

ANIMALS; ANTIGENS, CD; CELL SEPARATION; FLOW CYTOMETRY; HUMANS; LYMPHOCYTE ACTIVATION; RECEPTORS, ANTIGEN, T-CELL; T-LYMPHOCYTES, REGULATORY;

EID: 84881023853     PISSN: 15524922     EISSN: 15524930     Source Type: Journal    
DOI: 10.1002/cyto.a.22317     Document Type: Article

References (104)

1. Chu HH, Moon JJ, Kruse AC, Pepper M, Jenkins MK. Negative selection and peptide chemistry determine the size of naive foreign peptide-MHC class II-specific CD4+ T cell populations. J Immunol 2010;185:4705-4713.
2. Chu HH, Moon JJ, Takada K, Pepper M, Molitor JA, Schacker TW, Hogquist KA, Jameson SC, Jenkins MK. Positive selection optimizes the number and function of MHCII-restricted CD4+ T cell clones in the naive polyclonal repertoire. Proc Natl Acad Sci USA 2009;106:11241-11245.
3. Lee SJ, McLachlan JB, Kurtz JR, Fan D, Winter SE, Baumler AJ, Jenkins MK, McSorley SJ. Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development. PLoS Pathog 2012;8:e1002499.
4. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, Jenkins MK. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 2007;27:203-213.
5. 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;35:583-595.
6. Taniguchi RT, DeVoss JJ, Moon JJ, Sidney J, Sette A, Jenkins MK, Anderson MS. Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc Natl Acad Sci USA 2012;109:7847-7852.
7. Akue AD, Lee JY, Jameson SC. Derivation and maintenance of virtual memory CD8 T cells. J Immunol 2012;188:2516-2523.
8. Haluszczak C, Akue AD, Hamilton SE, Johnson LD, Pujanauski L, Teodorovic L, Jameson SC, Kedl RM. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J Exp Med 2009;206:435-448.
9. Hamilton SE, Schenkel JM, Akue AD, Jameson SC. IL-2 complex treatment can protect naive mice from bacterial and viral infection. J Immunol 2010;185:6584-6590.
10. Obar JJ, Khanna KM, Lefrancois L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 2008;28:859-869.
11. Day EB, Charlton KL, La Gruta NL, Doherty PC, Turner SJ. Effect of MHC class I diversification on influenza epitope-specific CD8+ T cell precursor frequency and subsequent effector function. J Immunol 2011;186:6319-6328.
12. Flesch IE, Woo WP, Wang Y, Panchanathan V, Wong YC, La Gruta NL, Cukalac T, Tscharke DC. Altered CD8(+) T cell immunodominance after vaccinia virus infection and the naive repertoire in inbred and F(1) mice. J Immunol 2010;184:45-55.
13. Kotturi MF, Scott I, Wolfe T, Peters B, Sidney J, Cheroutre H, von Herrath MG, Buchmeier MJ, Grey H, Sette A. Naive precursor frequencies and MHC binding rather than the degree of epitope diversity shape CD8+ T cell immunodominance. J Immunol 2008;181:2124-2133.
14. La Gruta NL, Rothwell WT, Cukalac T, Swan NG, Valkenburg SA, Kedzierska K, Thomas PG, Doherty PC, Turner SJ. Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion. J Clin Invest 2010;120:1885-1894.
15. Alanio C, Lemaitre F, Law HK, Hasan M, Albert ML. Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies. Blood 2010;115:3718-3725.
16. Kwok WW, Tan V, Gillette L, Littell CT, Soltis MA, LaFond RB, Yang J, James EA, DeLong JH. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. J Immunol 2012;188:2537-2544.
17. Legoux F, Debeaupuis E, Echasserieau K, De La Salle H, Saulquin X, Bonneville M. Impact of TCR reactivity and HLA phenotype on naive CD8 T cell frequency in humans. J Immunol 2010;184:6731-6738.
18. Ruckwardt TJ, Malloy AM, Gostick E, Price DA, Dash P, McClaren JL, Thomas PG, Graham BS. Neonatal CD8 T-cell hierarchy is distinct from adults and is influenced by intrinsic T cell properties in respiratory syncytial virus infected mice. PLoS Pathog 2011;7:e1002377.
19. Schmidt J, Neumann-Haefelin C, Altay T, Gostick E, Price DA, Lohmann V, Blum HE, Thimme R. Immunodominance of HLA-A2-restricted hepatitis C virus-specific CD8+ T cell responses is linked to naive-precursor frequency. J Virol 2011;85:5232-5236.
20. Pape KA, Kearney ER, Khoruts A, Mondino A, Merica R, Chen ZM, Ingulli E, White J, Johnson JG, Jenkins MK. Use of adoptive transfer of T-cell-antigen-receptor-transgenic T cell for the study of T-cell activation in vivo. Immunol Rev 1997;156:67-78.
21. Matsui K, Boniface JJ, Reay PA, Schild H, Fazekas de St Groth B, Davis MM. Low affinity interaction of peptide-MHC complexes with T cell receptors. Science 1991;254(5039):1788-1791.
22. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM. Phenotypic analysis of antigen-specific T lymphocytes. Science 1996;274:94-96.
23. Benlagha K, Weiss A, Beavis A, Teyton L, Bendelac A. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J Exp Med 2000;191:1895-1903.
24. Kasmar AG, van Rhijn I, Cheng TY, Turner M, Seshadri C, Schiefner A, Kalathur RC, Annand JW, de Jong A, Shires J, et al. CD1b tetramers bind alphabeta T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans. J Exp Med 2011;208:1741-1747.
25. Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, Koezuka Y, Kronenberg M. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med 2000;192:741-754.
26. Day CL, Seth NP, Lucas M, Appel H, Gauthier L, Lauer GM, Robbins GK, Szczepiorkowski ZM, Casson DR, Chung RT, et al. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J Clin Invest 2003;112:831-842.
27. Toebes M, Coccoris M, Bins A, Rodenko B, Gomez R, Nieuwkoop NJ, van de Kasteele W, Rimmelzwaan GF, Haanen JB, Ovaa H, et al. Design and use of conditional MHC class I ligands. Nat Med 2006;12:246-251.
28. Gredmark-Russ S, Cheung EJ, Isaacson MK, Ploegh HL, Grotenbreg GM. The CD8 T-cell response against murine gammaherpes virus 68 is directed toward a broad repertoire of epitopes from both early and late antigens. J Virol 2008;82:12205-12212.
29. Grotenbreg GM, Roan NR, Guillen E, Meijers R, Wang JH, Bell GW, Starnbach MN, Ploegh HL. Discovery of CD8+ T cell epitopes in Chlamydia trachomatis infection through use of caged class I MHC tetramers. Proc Natl Acad Sci USA 2008;105:3831-3836.
30. Kwok WW, Gebe JA, Liu A, Agar S, Ptacek N, Hammer J, Koelle DM, Nepom GT. Rapid epitope identification from complex class-II-restricted T-cell antigens. Trends Immunol 2001;22:583-588.
31. Novak EJ, Liu AW, Gebe JA, Falk BA, Nepom GT, Koelle DM, Kwok WW. Tetramer-guided epitope mapping: Rapid identification and characterization of immunodominant CD4+ T cell epitopes from complex antigens. J Immunol 2001;166:6665-6670.
32. Hadrup SR, Bakker AH, Shu CJ, Andersen RS, van Veluw J, Hombrink P, Castermans E, Thor Straten P, Blank C, Haanen JB, et al. Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods 2009;6:520-526.
33. Newell EW, Klein LO, Yu W, Davis MM. Simultaneous detection of many T-cell specificities using combinatorial tetramer staining. Nat Methods 2009;6:497-499.
34. Brosterhus H, Brings S, Leyendeckers H, Manz RA, Miltenyi S, Radbruch A, Assenmacher M, Schmitz J. Enrichment and detection of live antigen-specific CD4(+) and CD8(+) T cells based on cytokine secretion. Eur J Immunol 1999;29:4053-4059.
35. Kern F, Surel IP, Brock C, Freistedt B, Radtke H, Scheffold A, Blasczyk R, Reinke P, Schneider-Mergener J, Radbruch A, et al. T-cell epitope mapping by flow cytometry. Nat Med 1998;4:975-978.
36. Waldrop SL, Pitcher CJ, Peterson DM, Maino VC, Picker LJ. Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: Evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency. J Clin Invest 1997;99:1739-1750.
37. Assenmacher M, Schmitz J, Radbruch A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: Expression of interleukin-10 in interferon-gamma and in interleukin-4-expressing cells. Eur J Immunol 1994;24:1097-1101.
38. Jung T, Schauer U, Heusser C, Neumann C, Rieger C. Detection of intracellular cytokines by flow cytometry. J Immunol Methods 1993;159:197-207.
39. Manz R, Assenmacher M, Pfluger E, Miltenyi S, Radbruch A. Analysis and sorting of live cells according to secreted molecules, relocated to a cell-surface affinity matrix. Proc Natl Acad Sci USA 1995;92:1921-1925.
40. Brestrich G, Zwinger S, Fischer A, Schmuck M, Rohmhild A, Hammer MH, Kurtz A, Uharek L, Knosalla C, Lehmkuhl H, et al. Adoptive T-cell therapy of a lung transplanted patient with severe CMV disease and resistance to antiviral therapy. Am J Transplant 2009;9:1679-1684.
41. Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht K, Handgretinger R, Peters C, Schuster FR, Beck R, et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol 2006;134:64-76.
42. Mackinnon S, Thomson K, Verfuerth S, Peggs K, Lowdell M. Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. Blood Cells Mol Dis 2008;40:63-67.
43. Moosmann A, Bigalke I, Tischer J, Schirrmann L, Kasten J, Tippmer S, Leeping M, Prevalsek D, Jaeger G, Ledderose G, et al. Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells. Blood 2010;115:2960-2970.
44. Caruso A, Licenziati S, Corulli M, Canaris AD, De Francesco MA, Fiorentini S, Peroni L, Fallacara F, Dima F, Balsari A, et al. Flow cytometric analysis of activation markers on stimulated T cells and their correlation with cell proliferation. Cytometry 1997;27:71-76.
45. Chattopadhyay PK, Yu J, Roederer M. A live-cell assay to detect antigen-specific CD4+ T cells with diverse cytokine profiles. Nat Med 2005;11:1113-1117.
46. Frentsch M, Arbach O, Kirchhoff D, Moewes B, Worm M, Rothe M, Scheffold A, Thiel A. Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat Med 2005;11:1118-1124.
47. Kirchhoff D, Frentsch M, Leclerk P, Bumann D, Rausch S, Hartmann S, Thiel A, Scheffold A. Identification and isolation of murine antigen-reactive T cells according to CD154 expression. Eur J Immunol 2007;37:2370-2377.
48. Maino VC, Suni MA, Ruitenberg JJ. Rapid flow cytometric method for measuring lymphocyte subset activation. Cytometry 1995;20:127-133.
49. Mardiney M, 3rd, Brown MR, Fleisher TA. Measurement of T-cell CD69 expression: A rapid and efficient means to assess mitogen- or antigen-induced proliferative capacity in normals. Cytometry 1996;26:305-310.
50. Patino-Lopez G, Hevezi P, Lee J, Willhite D, Verge GM, Lechner SM, Ortiz-Navarrete V, Zlotnik A. Human class-I restricted T cell associated molecule is highly expressed in the cerebellum and is a marker for activated NKT and CD8+ T lymphocytes. J Neuroimmunol 2006;171:145-155.
51. Wehler TC, Karg M, Distler E, Konur A, Nonn M, Meyer RG, Huber C, Hartwig UF, Herr W. Rapid identification and sorting of viable virus-reactive CD4(+) and CD8(+) T cells based on antigen-triggered CD137 expression. J Immunol Methods 2008;339:23-37.
52. Wölfl M, Kuball J, Eyrich M, Schlegel PG, Greenberg PD. Use of CD137 to study the full repertoire of CD8+ T cells without the need to know epitope specificities. Cytometry A 2008;73A:1043-1049.
53. Wölfl M, Kuball J, Ho WY, Nguyen H, Manley TJ, Bleakley M, Greenberg PD. Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood 2007;110:201-210.
54. Yeh JH, Sidhu SS, Chan AC. Regulation of a late phase of T cell polarity and effector functions by Crtam. Cell 2008;132:846-859.
55. Zaunders JJ, Munier ML, Seddiki N, Pett S, Ip S, Bailey M, Xu Y, Brown K, Dyer WB, Kim M, et al. High levels of human antigen-specific CD4+ T cells in peripheral blood revealed by stimulated coexpression of CD25 and CD134 (OX40). J Immunol 2009;183:2827-2836.
56. Cebrian M, Yague E, Rincon M, Lopez-Botet M, de Landazuri MO, Sanchez-Madrid F. Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes. J Exp Med 1988;168:1621-1637.
57. Hara T, Jung LK, Bjorndahl JM, Fu SM. Human T cell activation. III. Rapid induction of a phosphorylated 28 kD/32 kD disulfide-linked early activation antigen (EA 1) by 12-o-tetradecanoyl phorbol-13-acetate, mitogens, and antigens. J Exp Med 1986;164:1988-2005.
58. Lanier LL, Buck DW, Rhodes L, Ding A, Evans E, Barney C, Phillips JH. Interleukin 2 activation of natural killer cells rapidly induces the expression and phosphorylation of the Leu-23 activation antigen. J Exp Med 1988;167:1572-1585.
59. Testi R, Phillips JH, Lanier LL. Leu 23 induction as an early marker of functional CD3/T cell antigen receptor triggering. Requirement for receptor cross-linking, prolonged elevation of intracellular [Ca++] and stimulation of protein kinase C. J Immunol 1989;142:1854-1860.
60. Sun S, Zhang X, Tough DF, Sprent J. Type I interferon-mediated stimulation of T cells by CpG DNA. J Exp Med 1998;188:2335-2342.
61. Tough DF, Sun S, Sprent J. T cell stimulation in vivo by lipopolysaccharide (LPS). J Exp Med 1997;185:2089-2094.
62. Bacher P, Schink C, Teutschbein J, O. K, Assenmacher M, Brakhage A, Scheffold A. Antigen-reactive T cell enrichment for direct, high-resolution analysis of the human naive and memory T helper cell repertoire. J Immunol 2013;190:3967-3976.
63. Schoenbrunn A, Frentsch M, Kohler S, Keye J, Dooms H, Moewes B, Dong J, Loddenkemper C, Sieper J, Wu P, et al. A converse 4-1BB and CD40 ligand expression pattern delineates activated regulatory T cells (Treg) and conventional T cells enabling direct isolation of alloantigen-reactive natural Foxp3+ Treg. J Immunol 2012;189:5985-5994.
64. Geiger R, Duhen T, Lanzavecchia A, Sallusto F. Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells. J Exp Med 2009;206:1525-1534.
65. Selin LK, Brehm MA, Naumov YN, Cornberg M, Kim SK, Clute SC, Welsh RM. Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity. Immunol Rev 2006;211:164-181.
66. Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM. Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 2013;38:373-383.
67. Grützkau A, Radbruch A. Small but mighty: How the MACS-technology based on nanosized superparamagnetic particles has helped to analyze the immune system within the last 20 years. Cytometry A 2010;77:643-647.
68. Miltenyi S, Muller W, Weichel W, Radbruch A. High gradient magnetic cell separation with MACS. Cytometry 1990;11:231-238.
69. Radbruch A, Recktenwald D. Detection and isolation of rare cells. Curr Opin Immunol 1995;7:270-273.
70. Thiel A, Scheffold A, Radbruch A. Immunomagnetic cell sorting-Pushing the limits. Immunotechnology 1998;4:89-96.
71. Campbell JD, Foerster A, Lasmanowicz V, Niemoller M, Scheffold A, Fahrendorff M, Rauser G, Assenmacher M, Richter A. Rapid detection, enrichment and propagation of specific T cell subsets based on cytokine secretion. Clin Exp Immunol 2010;163:1-10.
72. Veldman C, Stauber A, Wassmuth R, Uter W, Schuler G, Hertl M. Dichotomy of autoreactive Th1 and Th2 cell responses to desmoglein 3 in patients with pemphigus vulgaris (PV) and healthy carriers of PV-associated HLA class II alleles. J Immunol 2003;170:635-642.
73. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 2004;199:1567-1575.
74. Barnes E, Ward SM, Kasprowicz VO, Dusheiko G, Klenerman P, Lucas M. Ultra-sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8+ T cells. Eur J Immunol 2004;34:1570-1577.
75. Bodinier M, Peyrat MA, Tournay C, Davodeau F, Romagne F, Bonneville M, Lang F. Efficient detection and immunomagnetic sorting of specific T cells using multimers of MHC class I and peptide with reduced CD8 binding. Nat Med 2000;6:707-710.
76. Jang MH, Seth NP, Wucherpfennig KW. Ex vivo analysis of thymic CD4 T cells in nonobese diabetic mice with tetramers generated from I-A(g7)/class II-associated invariant chain peptide precursors. J Immunol 2003;171:4175-4186.
77. Keenan RD, Ainsworth J, Khan N, Bruton R, Cobbold M, Assenmacher M, Milligan DW, Moss PA. Purification of cytomegalovirus-specific CD8 T cells from peripheral blood using HLA-peptide tetramers. Br J Haematol 2001;115:428-434.
78. Lemaitre F, Viguier M, Cho MS, Fourneau JM, Maillere B, Kourilsky P, Van Endert PM, Ferradini L. Detection of low-frequency human antigen-specific CD4(+) T cells using MHC class II multimer bead sorting and immunoscope analysis. Eur J Immunol 2004;34:2941-2949.
79. Lucas M, Day CL, Wyer JR, Cunliffe SL, Loughry A, McMichael AJ, Klenerman P. Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells. J Virol 2004;78:7284-7287.
80. McDermott AB, Spiegel HM, Irsch J, Ogg GS, Nixon DF. A simple and rapid magnetic bead separation technique for the isolation of tetramer-positive virus-specific CD8 T cells. Aids 2001;15:810-812.
81. Roti M, Yang J, Berger D, Huston L, James EA, Kwok WW. Healthy human subjects have CD4+ T cells directed against H5N1 influenza virus. J Immunol 2008;180:1758-1768.
82. Scriba TJ, Purbhoo M, Day CL, Robinson N, Fidler S, Fox J, Weber JN, Klenerman P, Sewell AK, Phillips RE. Ultrasensitive detection and phenotyping of CD4+ T cells with optimized HLA class II tetramer staining. J Immunol 2005;175:6334-6343.
83. Jenkins MK, Chu HH, McLachlan JB, Moon JJ. On the composition of the preimmune repertoire of T cells specific for peptide-major histocompatibility complex ligands. Annu Rev Immunol 2010;28:275-294.
84. Tan AC, La Gruta NL, Zeng W, Jackson DC. Precursor frequency and competition dictate the HLA-A2-restricted CD8+ T cell responses to influenza A infection and vaccination in HLA-A2.1 transgenic mice. J Immunol 2011;187:1895-1902.
85. DeLong JH, Simpson KH, Wambre E, James EA, Robinson D, Kwok WW. Ara h 1-reactive T cells in individuals with peanut allergy. J Allergy Clin Immunol 2011;127:1211-1218 e3.
86. Kwok WW, Roti M, Delong JH, Tan V, Wambre E, James EA, Robinson D. Direct ex vivo analysis of allergen-specific CD4+ T cells. J Allergy Clin Immunol 2010;125:1407-1409 e1.
87. Wambre E, DeLong JH, James EA, LaFond RE, Robinson D, Kwok WW. Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J Allergy Clin Immunol 2012;129:544-551 e1-e7.
88. Kinnunen T, Nieminen A, Kwok WW, Narvanen A, Rytkonen-Nissinen M, Saarelainen S, Taivainen A, Virtanen T. Allergen-specific naive and memory CD4+ T cells exhibit functional and phenotypic differences between individuals with or without allergy. Eur J Immunol 2011;40:2460-2469.
89. Sabatino JJ Jr, Huang J, Zhu C, Evavold BD. High prevalence of low affinity peptide-MHC II tetramer-negative effectors during polyclonal CD4+ T cell responses. J Exp Med 2011;208:81-90.
90. Moon JJ, Dash P, Oguin TH, 3rd, McClaren JL, Chu HH, Thomas PG, Jenkins MK. Quantitative impact of thymic selection on Foxp3+ and Foxp3- subsets of self-peptide/MHC class II-specific CD4+ T cells. Proc Natl Acad Sci USA 2011;108:14602-14607.
91. Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio CW, Vegoe AL, Hsieh CS, Jenkins MK, Farrar MA. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 2008;28:112-121.
92. Bonvalet M, Moussu H, Wambre E, Ricarte C, Horiot S, Rimaniol AC, Kwok WW, Horak F, de Beaumont O, Baron-Bodo V, et al. Allergen-specific CD4+ T cell responses in peripheral blood do not predict the early onset of clinical efficacy during grass pollen sublingual immunotherapy. Clin Exp Allergy 2012;42:1745-1755.
93. Palomares O, Ruckert B, Jartti T, Kucuksezer UC, Puhakka T, Gomez E, Fahrner HB, Speiser A, Jung A, Kwok WW, et al. Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance. J Allergy Clin Immunol 2011;129:510-520 e1-e9.
94. Van Overtvelt L, Wambre E, Maillere B, von Hofe E, Louise A, Balazuc AM, Bohle B, Ebo D, Leboulaire C, Garcia G, et al. Assessment of Bet v 1-specific CD4+ T cell responses in allergic and nonallergic individuals using MHC class II peptide tetramers. J Immunol 2008;180:4514-4522.
95. Ebinuma H, Nakamoto N, Li Y, Price DA, Gostick E, Levine BL, Tobias J, Kwok WW, Chang KM. Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J Virol 2008;82:5043-5053.
96. Pido-Lopez J, Kwok WW, Mitchell TJ, Heyderman RS, Williams NA. Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue. PLoS Pathog 2011;7:e1002396.
97. Vukmanovic-Stejic M, Sandhu D, Sobande TO, Agius E, Lacy KE, Riddell N, Montez S, Dintwe OB, Scriba TJ, Breuer J, et al. Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans. J Immunol 2013;190:977-986.
98. Angin M, King M, Altfeld M, Walker BD, Wucherpfennig KW, Addo MM. Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers. Aids 2012;26:2112-2115.
99. Long SA, Walker MR, Rieck M, James E, Kwok WW, Sanda S, Pihoker C, Greenbaum C, Nepom GT, Buckner JH. Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects. Eur J Immunol 2009;39:612-620.
100. Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007;110:2983-2990.
101. Tran DQ, Andersson J, Hardwick D, Bebris L, Illei GG, Shevach EM. Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood 2009;113:5125-5133.
102. Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM. GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009;106:13445-13450.
103. Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009;106:13439-13444.
104. Litjens NH, Boer K, Betjes MG. Identification of circulating human antigen-reactive CD4+ FOXP3+ natural regulatory T cells. J Immunol 2012;188:1083-1090.