Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules

Texier, Catherine; Pouvelle‐Moratille, Sandra; Busson, Marc; Charron, Dominique; Ménèz, Andre; Maillère, Bernard

doi:10.1002/1521-4141(200106)31:6<1837::aid-immu1837>3.0.co;2-h

Cited by 60 publications

(94 citation statements)

References 38 publications

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“…With this aim, we assessed the relative efficiency of untagged and His-tagged ESO peptides to bind to DR52b using a previously described competition assay (13). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Ayyoub

Dojcinovic

Pignon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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MHC-peptide tetramers have become essential tools for T-cell analysis, but few MHC class II tetramers incorporating peptides from human tumor and self-antigens have been developed. Among limiting factors are the high polymorphism of class II molecules and the low binding capacity of the peptides. Here, we report the generation of molecularly defined tetramers using His-tagged peptides and isolation of folded MHC/peptide monomers by affinity purification. Using this strategy we generated tetramers of DR52b (DRB3*0202), an allele expressed by approximately half of Caucasians, incorporating an epitope from the tumor antigen NY-ESO-1. Molecularly defined tetramers avidly and stably bound to specific CD4 + T cells with negligible background on nonspecific cells. Using molecularly defined DR52b/ NY-ESO-1 tetramers, we could demonstrate that in DR52b + cancer patients immunized with a recombinant NY-ESO-1 vaccine, vaccineinduced tetramer-positive cells represent ex vivo in average 1:5,000 circulating CD4 + T cells, include central and transitional memory polyfunctional populations, and do not include CD4 + CD25 + CD127 − regulatory T cells. This approach may significantly accelerate the development of reliable MHC class II tetramers to monitor immune responses to tumor and self-antigens.S oluble MHC-peptide tetramers, allowing the direct visualization, characterization, and isolation of antigen-specific T cells, have become essential tools for T-cell analysis. MHC class I tetramers incorporating short CTL peptide epitopes, originally developed by Altman and Davis (1) have been generated for a large number of murine and human alleles, incorporating a variety of peptides of microbial, tumor, and self-antigen origin (2). The development of MHC class II tetramers, however, and particularly of those incorporating peptides from tumor and self-antigens, has been far less successful (3-5). One limiting factor is the high polymorphism of the human MHC class II molecules, especially those encoded by the DRB1 locus, the most frequently studied. Another limiting factor is the binding affinity of antigenic peptides derived from tumor and self-antigens, which is generally lower than that of peptides from pathogens.NY-ESO-1 (ESO), a tumor-specific antigen of the cancer/testis group frequently expressed in tumors of different histological types (6), is an important candidate for the development of generic cancer vaccines (7). In a recent vaccination trial using a recombinant ESO protein (rESO) administered with Montanide ISA 51 and CpG ODN 7909, we have observed induction of CD4 + T cell responses in all vaccinated patients (8). By assessing vaccineinduced CD4 + T cells, we have identified an immunodominant epitope , core region ESO 123-137 ) restricted by HLADR52b (DRB3*0202), an allele expressed by half of Caucasians (9). DRB3-, DRB4-, and DRB5-encoded molecules are less polymorphic than those encoded by DRB1, and are therefore attractive candidates for the development of generic MHC class II tetramers.Our initial attempts to const...

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“…With this aim, we assessed the relative efficiency of untagged and His-tagged ESO peptides to bind to DR52b using a previously described competition assay (13). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Ayyoub

Dojcinovic

Pignon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Purification of HLA-DR molecules and peptide-binding assays was performed, as previously described (38,39). Briefly, HLA-DR molecules purified from EBV homozygous cell lines by affinity chromatography were incubated with different concentrations of competitor peptide and an appropriate biotinylated peptide.…”

Section: Hla-dr Peptide-binding Assaysmentioning

confidence: 99%

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

Fournel

Neichel

Dali

et al. 2003

The Journal of Immunology

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We have previously reported that peptide 88-99 of histone H4 represents a minimal T cell epitope recognized by Th cells from nonautoimmune BALB/c (H-2d/d) mice immunized with nucleosomes. In this study, we tested a panel of overlapping peptides spanning the whole sequences of H4 and H3 for recognition by CD4+ T cells from unprimed (New Zealand Black (NZB) × New Zealand White (NZW))F1 lupus mice (H-2d/z). None of the 11 H4 peptides was recognized by CD4+ T cells from (NZB × NZW)F1 mice. In contrast, these cells proliferated and secreted IL-2, IL-10, and IFN-γ upon ex vivo stimulation with H3 peptides representing sequences 53-70, 64-78, and 68-85. Peptides 56-73 and 61-78 induced the production of IFN-γ and IL-10, respectively, without detectable proliferation, suggesting that they may act as partial agonist of the TCR. Th cells from unprimed BALB/c mice and other lupus-prone mice such as SNF1 (H-2d/q) and MRL/lpr (H-2k/k) mice did not recognize any peptides present within the H3 region 53-85. We further demonstrated that immunization of normal BALB/c mice with syngeneic liver nucleosomes and spleen apoptotic cells, but not with nonapoptotic syngeneic cells, induced Th cell responses against several peptides of the H3 region 53-85. Moreover, we found that this conserved region of H3, which is accessible at the surface of nucleosomes, is targeted by Abs from (NZB × NZW)F1 mice and lupus patients, and contains motifs recognized by several distinct HLA-DR molecules. It might thus be important in the self-tolerance breakdown in lupus.

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“…HLA-DR molecules were purified from homologous EBV cell lines by affinity chromatography using the monomorphic mAb L243 [39,40]. The binding to HLA-DR molecules was assessed by competitive ELISA as previously reported [39,40].…”

Section: Hla II Peptide-binding Assaysmentioning

confidence: 99%

“…The binding to HLA-DR molecules was assessed by competitive ELISA as previously reported [39,40]. Peptide concentration that prevented binding of 50% of the labeled peptide (IC 50 ) was evaluated.…”

Section: Hla II Peptide-binding Assaysmentioning

confidence: 99%

“…In the Vpr protein (Table 2), multiple peptides exhibited binding activity comparable to that of the reference peptides. Vpr peptides (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79) were retained for further investigations because they bound to at least three molecules and encompassed different peptide regions. Selected Tat and Vpr peptides were then investigated for their capacity to prime in vitro a CD4 1 T-cell response.…”

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Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

et al. 2008

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Recent studies have suggested including nonstructural proteins as Tat and Vpr in HIV vaccines. However, little is known about the CD4 1 T-cell response that these small proteins induce in humans. We have therefore evaluated these responses by in vitro priming experiments of CD4 1 T lymphocytes harvested in healthy donors. In the Tat protein, only one peptide primed CD4 1 T cells of eight HLA unrelated healthy donors. T cells induced by this peptide recognized immature DC loaded with the native Tat protein and are restricted by multiple HLA-DR molecules, in agreement with its binding capacity. This peptide was therefore processed in an appropriate manner and was highly immunoprevalent. CD4 1 T-cell response to Vpr peptides was more disperse and involved six different peptides depending on the HLA-DR molecules of the donors. Two overlapping peptides were T-cell stimulating in at least half of the donors. T-cell response to Vpr in multiple donors is the result of a combination of several CD4 1 T-cell epitopes with good to moderate immunoprevalence. Altogether, our results show that the frequency of responders to HIV Tat or Vpr proteins relies on one or multiple CD4 1 T-cell epitopes, respectively.Key words: CD4 1 T cells . Epitopes . HIV . HLA class II . MHC IntroductionTwenty years after the discovery of HIV, an effective prophylactic or therapeutic vaccine is still not available. Current approaches are mainly based on the introduction of structural antigens into viral vectors, their combination with strong adjuvants or their injection as DNA vaccine [1]. Alternative or complementary approaches aim at neutralizing accessory or regulatory proteins because they disturb the immune system and counteract its beneficial role [2,3]. Transacting protein (Tat) is a small regulatory protein that is expressed early in the viral cycle and is essential for viral replication [4]. Besides its transactivating activity, Tat exerts a wide range of activities. It diminishes T-cell function and provokes immunosuppression [5]. It enhances DC maturation [6] and exhibits an adjuvant activity [7]. Tat also regulates apoptosis of infected and noninfected cells by a variety of possible mechanisms including downregulation of Bcl-2 and upregulation of . In contrast to Tat, the Virus protein R (Vpr) accessory protein is expressed late in the virus cycle and is also essential for in vivo viral replication [9]. Vpr impairs DC maturation and T-cell activation [10]. Both Vpr and Tat proteins could be targeted by CD8 1 T-cells in seropositive donors [11][12][13][14][15] and hence constitute potential candidates to elicit an HIV-specific cellular response. Multiple forms of Tat peptides elicit neutralizing antibodies in monkeys and lead to promising but controversial results in terms of protection [16][17][18]. It is not known whether immune response specific for accessory or regulatory HIV proteins leads to immune escape, which has a fitness cost on the virus. Moreover, despite the requirement of CD4 1 T lymphocytes to sustain both humoral and cel...

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Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules

Cited by 60 publications

References 38 publications

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

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Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules

Cited by 60 publications

References 38 publications

Monitoring of NY-ESO-1 specific CD4 + T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Monitoring of NY-ESO-1 specific CD4 + T cells using molecularly defined MHC class II/His-tag-peptide tetramers

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

Immunoprevalence of the CD4+ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

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Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Monitoring of NY-ESO-1 specific CD4 ⁺ T cells using molecularly defined MHC class II/His-tag-peptide tetramers

Immunoprevalence of the CD4⁺ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively