Transgenic mice with a diverse human T cell antigen receptor repertoire

Li, Liang Ping; Lampert, J. Christoph; Chen, Xiaojing; Leitão, Catarina; Popović, Jelena; Müller, Werner; Blankenstein, Thomas

doi:10.1038/nm.2197

Cited by 107 publications

(91 citation statements)

References 34 publications

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“…13 Although CD8 ϩ T cells responded to nonspecific polyclonal stimulation through CD3/CD28, no TEL-AML1-specific CD8 ϩ T-cell response could be detected. Therefore, the peptide was anchor-modified by exchanging the Cterminal methionine for valine (TEL-AML1-9V).…”

Section: An Anchor Modification Is Needed To Render the Described Telmentioning

confidence: 92%

“…13 They are transgenic for entire human TCR-␣ and TCR-␤ gene loci, as well as for HHD molecule, 14 and deficient for the murine Tcr-␣ and -␤ chains, as well as for murine ␤2m…”

Section: Micementioning

confidence: 99%

“…14 Previously, we showed that functional specific CD8 ϩ T cells against a variety of described HLA-A*0201-restricted epitopes derived from human tumor antigens could be induced in these mice. 13 Therefore, they provide an exquisite tool for testing the immunogenicity of potential human tumor antigen epitopes, as well as for isolation of therapeutic human TCRs. Surprisingly, we found that the described TEL-AML1 peptide exhibited a very low HLA-A*0201 binding affinity and an anchor-modification had to be introduced to render the peptide immunogenic.…”

Section: Introductionmentioning

confidence: 99%

“…12 As a potential source of TCRs specific for the described TEL-AML1 epitope, we have used a mouse transgenic model for the entire human TCR-␣ and TCR-␤ gene loci and human MHC class I, termed ABabDII mice. 13 The human TCRs in these mice are HLA-A*0201-restricted, because the mice carry HHD molecule as a transgene, which consists of the HLA-A*0201 molecule with the murine H2-D b ␣3 domain to enable binding to murine CD8 coreceptor, additionally fused to human ␤2-microglobulin. 14 Previously, we showed that functional specific CD8 ϩ T cells against a variety of described HLA-A*0201-restricted epitopes derived from human tumor antigens could be induced in these mice.…”

mentioning

confidence: 99%

“…Mice were immunized subcutaneously in the tail base either with 100 nmol (ϳ 100 g) of the nonamer peptides, 50 nmol (ϳ 50 g) of the highly immunogenic decamer peptide Melan-A/MART-1, or 40 nmol (125-130 g) of the long peptides, diluted in 100 L PBS with Յ 10% vol/vol DMSO (SigmaAldrich), mixed with 50 g CpG 1826 (TIB MOLBIOL) and emulsified in 100 L of incomplete Freund adjuvant (IFA; Sigma-Aldrich), and subsequently boosted (once or twice) with the same peptide emulsions in 2-week intervals, as described. 13,21 Pooled splenocytes and inguinal LN cells were analyzed 10-14 days after the boosting. Unspecific peptides used for restimulation in control experiments were Melan-A/MART-1 or NY-BR-1-960 SLSKILDTV (designated NY-BR-1).…”

mentioning

confidence: 99%

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The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

Popović

Kloetzel

et al. 2011

Blood

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Adoptive therapy with T-cell receptor (TCR)-engineered T cells is a promising approach in cancer treatment. While usage of T cells specific for tumor-associated antigens (TAAs) can lead to serious side effects because of autoimmunity, targeting true tumor-specific mutations, such as the products of translocations in leukemias, should reduce such a risk. A potentially ideal target might be the chimeric protein TEL-AML1, which results from the chromosomal translocation 12;21 and represents the most common fusion gene in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Within the fusion region of TEL-AML1, a single epitope has been described by reverse immunology as immunogenic in HLA-A*0201 restriction settings. As a potential source of TCRs specific for this TEL-AML1 epitope, we have used mice expressing a human TCR-␣␤ repertoire and human MHC class I. Surprisingly, we have found that, although a specific functional CD8 ؉ T-cell response against this peptide could be evoked, the described epitope was in fact not endogenously processed. Analyses done with a potent antigen-presenting cell line, as well as with purified human proteasomes, support the conclusion that this peptide cannot be proposed as a potential target in immunotherapy of ALL in HLA-A*0201-restricted fashion. (Blood. 2011; 118(4):946-954) IntroductionImmunotherapy of cancer through adoptive transfer of genemodified T cells is a promising approach 1-3 ; however, the choice of target antigen is decisive for its success. 4 Although targeting tumor-associated self-antigens is an approach applicable to a variety of tumors, serious side effects are occasionally seen. Adoptive transfer of autologous peripheral lymphocytes genetically engineered to express TCRs specific for melanocyte differentiation antigens Melan-A/MART-1 and gp100 in melanoma patients led to a partial clinical response, accompanied by autoimmune attack against skin, retina, and inner ear. 5 Targeting ERBB2, which is overexpressed in a variety of tumors, through chimeric antigen receptor (CAR)-transduced lymphocytes in a colon cancer patient resulted in a serious adverse event, because of recognition of low levels of ERBB2 on normal lung cells. 6 Targeting true tumor specific mutations, such as the products of translocations in leukemias, should reduce such a risk of autoimmunity. The chimeric protein TEL-AML1, resulting from the chromosomal translocation 12;21 represents the most common fusion gene in childhood BCP-ALL, 7 which places it among principal target candidates. Furthermore, because the TEL-AML1 fusion protein is an important transforming factor in leukemogenesis, 8,9 selection of antigen-loss variants is less likely to occur.A nonamer peptide derived from the TEL-AML1 fusion region has been described as immunogenic in HLA-A*0201 restriction settings. 10 Using reverse immunology approach, 11 a peptide which binds to HLA-A*0201 was identified. The peptide was used to induce cytotoxic T-cell (CTL) lines, which recognized autologous leukemic cells and the leukemi...

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Section: An Anchor Modification Is Needed To Render the Described Telmentioning

confidence: 92%

“…13 They are transgenic for entire human TCR-␣ and TCR-␤ gene loci, as well as for HHD molecule, 14 and deficient for the murine Tcr-␣ and -␤ chains, as well as for murine ␤2m…”

Section: Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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