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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 2/2010

01-02-2010 | Review

Multimer technologies for detection and adoptive transfer of antigen-specific T cells

Authors: Rosaely Casalegno-Garduño, Anita Schmitt, Junxia Yao, Xinchao Wang, Xun Xu, Mathias Freund, Michael Schmitt

Published in: Cancer Immunology, Immunotherapy | Issue 2/2010

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Abstract

Identification and purification of antigen-specific T cells without altering their functional status are of high scientific and clinical interest. Staining with major histocompatibility complex (MHC)-peptide multimers constitutes a very powerful method to study antigen-specific T-cell subpopulations, allowing their direct visualization and quantification. MHC-peptide multimers, such as dimers, tetramers, pentamers, streptamers, dextramers and octamers have been used to evaluate the frequency of CD8+ T cells, specific for tumor/leukemia-associated antigens as well as for viral antigens, e.g., CMVpp65 and EBV-EBNA. Moreover, MHC-peptide multimers have been used for rapid and efficient ex vivo isolation and expansion of T cells. A recent development in the field of MHC-peptide multimers led to the purification of CD8+ T cells specific for leukemia antigens. This might help to select leukemia-specific donor lymphocyte infusions (DLIs), thus allowing dissection of the noxious graft-versus-host disease (GvHD) from beneficial anti-viral and even anti-leukemic effects. This review covers different types of MHC-peptide multimers and their applications, as well as the impact that multimers might have on further development of DLIs.
Literature
1.
Hebart H, Rauser G, Stevanovic S et al (2003) A CTL epitope from human cytomegalovirus IE1 defined by combining prediction of HLA binding and proteasomal immune responses in patients after allogeneic stem cell transplantation. Exp Hematol 31:966–973CrossRefPubMed
2.
Manley TJ, Luy L, Jones T et al (2004) Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection. Blood 104:1075–1082CrossRefPubMed
3.
Grigoleit GU, Kapp M, Hebart H et al (2007) Dendritic cell vaccination in allogeneic stem cell recipients: induction of human cytomegalovirus (HCMV)-specific cytotoxic T-lymphocyte responses even in patients receiving a transplant from an HCMV-seronegative donor. J Infect Dis 196:699–704CrossRefPubMed
4.
Chattopadhyay PK, Hogerkorp CM, Roederer M (2008) A chromatic explosion: the development and future of multiparameter flow cytometry. Immunology 125:441–449CrossRefPubMed
5.
Duplan V, Suberbielle E, Napper CE et al (2007) Tracking antigen-specific CD8+ T cells in the rat using MHC class I multimers. J Immunol Methods 320:30–39CrossRefPubMed
6.
Svensson A, Nordström I, Sun JB, Eriksson K (2005) Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet. J Immunol 174:6266–6273PubMed
7.
Binder RJ, Srivastava PK (2005) Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nat Immunol 6:593–599CrossRefPubMed
8.
Knabel M, Franz TJ, Schiemann M et al (2002) Reversible MHC multimer staining for functional isolation of T-cell populations and effective adoptive transfer. Nat Med 8:631–637CrossRefPubMed
9.
Batard P, Peterson DA, Devêvre E et al (2006) Dextramers: new generation of fluorescent MHC class I/peptide multimers for visualization of antigen-specific CD8+ T cells. J Immunol Methods 310:136–148CrossRefPubMed
10.
Guillaume P, Legler DF, Boucheron N et al (2003) Soluble major histocompatibility complex-peptide octamers with impaired CD8 binding selectively induce FAS-dependent apoptosis. J Biol Chem 278:4500–4509CrossRefPubMed
11.
Schneck JP (2000) Monitoring antigen-specific T cells using MHC-Ig dimers. Immunol Invest 29:163–169CrossRefPubMed
12.
Dal Porto J, Johansen TE, Catipović B et al (1993) A soluble divalent class I major histocompatibility complex molecule inhibits alloreactive T cells at nanomolar concentrations. Proc Natl Acad Sci USA 90:6671–6675CrossRefPubMed
13.
Greten TF, Schneck JP (2002) Development and use of multimeric major histocompatibility complex molecules. Clin Diagn Lab Immunol 9:216–220PubMed
14.
Neudorfer J, Schmidt B, Huster KM et al (2007) Reversible HLA multimers (streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens. J Immunol Methods 320:119–131CrossRefPubMed
15.
Altman JD, Moss PA, Goulder PJ et al (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94–96CrossRefPubMed
16.
Doherty PC, Christensen JP (2000) Accessing complexity: the dynamics of virus-specific T-cell responses. Annu Rev Immunol 18:561–592CrossRefPubMed
17.
Wooldridge L, Lissina A, Cole D et al (2009) Tricks with tetramers: how to get the most from multimeric peptide-MHC. Immunology 126:147–164CrossRefPubMed
18.
Junttila MR, Saarinen S, Schmidt T et al (2005) Single-step Strep-tag purification for the isolation and identification of protein complexes from mammalian cells. Proteomics 5:1199–1203CrossRefPubMed
19.
Newell EW, Klein LO, Yu W, Davis MM (2009) Simultaneous detection of many T-cell specificities using combinatorial tetramer staining. Nat Methods 6:497–499CrossRefPubMed
20.
Hadrup SR, Bakker AH, Shu CJ et al (2009) Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods 6:520–526CrossRefPubMed
21.
Hardrup SR, Toebes M, Rodenko B et al (2009) High-throughput T-cell epitope discovery through MHC peptide exchange. Methods Mol Biol 524:383–405CrossRef
22.
Bakker AH, Hoppes R, Linnemann C et al (2008) Conditional MHC class I ligands and peptide exchange technology for the human MHC gene products HLA-A1, -A3, -A11, and -B7. Proc Natl Acad Sci USA 105:3825–3830CrossRefPubMed
23.
Barnes E, Ward SM, Kasprowicz VO et al (2004) Ultra-sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8+ T cells. Eur J Immunol 34:1570–1577CrossRefPubMed
24.
Harcourt GC, Scriba TJ, Semmo N et al (2006) Identification of key peptide-specific CD4+ T cell responses to human cytomegalovirus: implications for tracking antiviral populations. Clin Exp Immunol 146:203–210CrossRefPubMed
25.
Scriba TJ, Purbhoo M, Day CL et al (2005) Ultrasensitive detection and phenotyping of CD4+ T cells with optimized HLA class II tetramer staining. J Immunol 175:6334–6343PubMed
26.
Melenhorst JJ, Scheinberg P, Chattopadhyay PK et al (2008) High avidity myeloid leukemia-associated antigen-specific CD8+ T cells preferentially reside in the bone marrow. Blood 113:2238–2244CrossRefPubMed
27.
Bouquié R, Bonnin A, Bernardeau K et al (2009) A fast and efficient HLA multimer-based sorting procedure that induces little apoptosis to isolate clinical grade human tumor-specific T lymphocytes. Cancer Immunol Immunother 58:553–566CrossRefPubMed
28.
Greten TF, Slansky JE, Kubota R et al (1998) Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19-specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc Natl Acad Sci USA 95:7568–7573CrossRefPubMed
29.
Lee PP, Yee C, Savage PA et al (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nature Med 5:677–685CrossRefPubMed
30.
Busch DH, Pamer EG (1998) MHC class I/peptide stability: implications for immunodominance, in vitro proliferation, and diversity of responding CTL. J Immunol 160:4441–4448PubMed
31.
Keenan RD, Ainsworth J, Khan N et al (2001) Purification of cytomegalovirus-specific CD8 T cells from peripheral blood using HLA-peptide tetramers. Br J Haematol 115:428–434CrossRefPubMed
32.
Appay V, Nixon DF, Donahoe SM et al (2000) HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63–75CrossRefPubMed
33.
Choi EM, Chen JL, Wooldridge L et al (2003) High avidity antigen-specific CTL identified by CD8-independent tetramer staining. J Immunol 171:5116–5123PubMed
34.
Oelke M, Maus MV, Didiano D et al (2003) Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. Nat Med 9:619–624CrossRefPubMed
35.
Rauser G, Einsele H, Sinzger C et al (2003) Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into allogeneic stem cell transplant recipients. Blood 103:3565–3572CrossRefPubMed
36.
Widmann T, Sester U, Gartner BC et al (2008) Levels of CMV-specific CD4 T cells are dynamic and correlate with CMV viremia after allogeneic stem cell transplantation. PLoS One 3:1–9CrossRef
37.
Savage PA, Boniface JJ, Davis MM (1999) A kinetic basis for T-cell receptor repertoire selection during an immune response. Immunity 10:485–492CrossRefPubMed
38.
Britten CM, Gouttefangeas C, Welters MJ et al (2008) The CIMT-monitoring panel: a two-step approach to harmonize the enumeration of antigen-specific CD8(+) T lymphocytes by structural and functional assays. Cancer Immunol Immunother 57:258–285
39.
Britten CM, Janetzki S, Ben-Porat L et al (2009) Harmonization guidelines for HLA-peptide multimer assays derived from results of a large-scale international proficiency panel of the Cancer Vaccine Consortium. Cancer Immunol Immunother 58:1701–1713CrossRefPubMed
40.
41.
Yao J, Bechter C, Wiesneth M et al (2008) Multimer staining of CMVpp65-specific T cells for diagnosis and therapeutic purpose—a comparative study. Clin Infect Dis 46:96–105CrossRef
42.
Casares S, Hurtado A, McEvoy RC et al (2002) Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide-MHC class II chimera. Nat Immunol 3:383–391CrossRefPubMed
43.
Reijonen H, Novak EJ, Kochik S et al (2002) Detection of GAD65-specific T cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. Diabetes 51:1375–1382CrossRefPubMed
44.
Cobbold M, Khan N, Pourgheysari B et al (2005) Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med 202:379–386CrossRefPubMed
45.
Marmont AM, Horowitz MM, Gale RP et al (1991) T-cell depletion of HLA-identical transplants in leukemia. Blood 78:2120–2130PubMed
46.
Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112:4371–4383CrossRefPubMed
47.
Kolb HJ, Schattenberg A, Goldman JM et al (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041–2050PubMed
48.
Viola A, Lanzavecchia A (1996) T-cell activation determined by T-cell receptor number and tunable thresholds. Science 273:104–106CrossRefPubMed
49.
Sykulev Y, Joo M, Vturina I et al (1996) Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T-cell response. Immunity 4:565–571CrossRefPubMed
50.
Roback JD (2006) Vaccine-enhanced donor lymphocyte infusion. Hematology 486–491
51.
Boeckh M, Nichols WG, Papanicolaou G et al (2003) Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant 9:543–558CrossRefPubMed
52.
Langston AA, Redei I, Caliendo AM et al (2002) Development of drug-resistant herpes simplex virus infection after haploidentical hematopoietic progenitor cell transplantation. Blood 99:1085–1088CrossRefPubMed
53.
Levy RB, Jones M, Cray C (1990) HSV-1 enhances GvHR-associated parent anti-F1 alloreactivity in vivo and in vitro. Cell Immunol 129:1–12CrossRefPubMed
54.
Boeckh M, Leisenring W, Riddell SR et al (2003) Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101:407–414CrossRefPubMed
55.
Kolb HJ, Schmid A, Barret AJ, Schendel DJ (2004) Graft-versus-leukemia reactions in allogeneic chimeras. Blood 103:767–776CrossRefPubMed
56.
Riddell SR, Watanabe KS, Goodrich JM et al (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T-cell clones. Science 257:238–241CrossRefPubMed
57.
Tiberghien P, Ferrand C, Lioure B et al (2001) Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 97:63–72CrossRefPubMed
58.
Einsele H, Roosnek E, Rufer N et al (2002) Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 99:3916–3922CrossRefPubMed
59.
Walter EA, Greenberg PD, Gilbert MJ et al (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333:1038–1044CrossRefPubMed
60.
Mandigers CMPW, Verdonck LF, Meijerink JPP et al (2003) Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapse after allogeneic stem cell transplantation. Bone Marrow Transplant 32:1159–1163CrossRefPubMed
61.
Mackinnon S, Papadopoulos EB, Carabasi MH et al (1995) Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 86:1261–1268PubMed
62.
Bonini C, Ferrari G, Verzelletti S et al (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft versus leukemia. Science 276:1719–1724CrossRefPubMed
63.
Thomis DC, Marktel S, Bonini C et al (2001) A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 97:1249–1257CrossRefPubMed
64.
Molldrem JJ, Lee PP, Wang C et al (2000) Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 6:1018–1023CrossRefPubMed
65.
Wang X, Schmitt A, Germeroth L et al (2009) Generation of leukemia antigen-specific donor lymphocyte infusions powered by streptamer-based selection. Bone Marrow Transplant 43:S73
66.
Schmitt A, Tonn T, Busch DH et al (2009) Adoptive transfer and consequential selective reconstitution of streptamers-selected cytomegalovirus-specific CD8+ T cells leads to enduring virus clearance in patients after allogeneic stem cell transplantation. Bone Marrow Transplant 43:S246
Metadata
Title
Multimer technologies for detection and adoptive transfer of antigen-specific T cells
Authors
Rosaely Casalegno-Garduño
Anita Schmitt
Junxia Yao
Xinchao Wang
Xun Xu
Mathias Freund
Michael Schmitt
Publication date
01-02-2010
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 2/2010
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-009-0778-4

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