Recognition of core and flanking amino acids of MHC class II-bound peptides by the T cell receptor

Sant’Angelo, Derek B.; Robinson, Eve; Janeway, Charles A.; Denzin, Lisa K.

doi:10.1002/1521-4141(200209)32:9<2510::aid-immu2510>3.0.co;2-q

Cited by 62 publications

(47 citation statements)

References 39 publications

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“…This finding is also in agreement with studies of immunogenic T cell epitopes published by others (23)(24)(25). With the goal to define particular amino acid sequences that would generally increase p͞HLA-DR4 stability, we analyzed how substitution of each of these seven positions, one by one with each of the other 19 naturally occurring amino acids, would influence the reactivity of the murine T cell hybridoma clones (Fig.…”

Section: Discussionsupporting

confidence: 85%

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Durinovic‐Belló

Rosinger

Ja³

et al. 2006

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

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Recently, we have identified proinsulin (P-Ins)73-90 as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with ␤-islet cell autoimmunity and of HLA-DR4͞CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)͞HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFN␥ in response to P-Ins73-90. This finding is compatible with the previously detected regulatory cytokine pattern in subjects with ␤-cell autoimmunity. However, added N-or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins 73-90-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with ␤-islet cell autoimmunity or recent-onset type 1 diabetes.Foxp3 ͉ HLA-DRB1*0401 ͉ type 1 diabetes P roinsulin (P-Ins) is considered an important autoantigen in type 1 diabetes (T1D), because it is the only truly ␤-cellspecific target, and because autoreactivity to P-Ins is very common in T1D patients with the HLA-DRB1*0401 (DR4) DQ8 haplotype (1-6). The differences distinguishing autoreactive from foreign antigen reactive T cell responses to the same immunogenic epitope are still largely unknown (7). To understand the structural requirements for activation of self-reactive P-Ins 73-90 -specific T cells in T1D autoimmunity, we have isolated a Foxp3-positive CD4 ϩ T cell clone from a DR4-homozygous T1D patient and compared the fine specificity of this T cell receptor to those of two murine T cell hybridoma clones derived from HLA-DR4 transgenic mice, in which this epitope is a foreign antigen (8). P-Ins 73-90 is situated at the C terminus of the C peptide and also covers the enzymatic cleavage site of the insulin A chain (8). This site is proteolytically destroyed during the maturation of insulin before secretion and is, therefore, an indication that Proinsulin and not Insulin may be the actual autoantigenic target in T1D.In human studies using purified CD4 ϩ T cells from HLA-DR4-positive subjects with islet autoimmunity, P-Ins 73-90 was also identified as an immunodominant epitope. This epitope was recognized by approximately two thirds of autoantibody-positive subjects, one third of recently diagnosed T1D patients, and a few control subjects (5, 9). The cytokines seen in response to P-Ins 73-90 were predominantly IL-4 and IL-10 in subjects with ␤-cell autoimmunity (9). Moreover, in a consecutive follow up of three high-risk individuals, ...

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Section: Discussionsupporting

confidence: 85%

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Durinovic‐Belló

Rosinger

Ja³

et al. 2006

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

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“…This processing complexity together with the fact that MHCII molecules bind peptides of different yet overlapping lengths, makes the generation of models for the prediction of MHCII-antigen processing difficult. Nevertheless, recent reports indicate the existence of conserved regions flanking the core CD4 T-cell epitopes that are related to antigen processing rather than peptide-MHC interaction (Sant'Angelo et al 2002). Moreover, some reports argue that they may contribute to immunogeneicity as well (Carson et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Enhancement to the RANKPEP resource for the prediction of peptide binding to MHC molecules using profiles

et al. 2004

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We introduced previously an on-line resource, RANKPEP that uses position specific scoring matrices (PSSMs) or profiles for the prediction of peptide-MHC class I (MHCI) binding as a basis for CD8 T-cell epitope identification. Here, using PSSMs that are structurally consistent with the binding mode of MHC class II (MHCII) ligands, we have extended RANKPEP to prediction of peptide-MHCII binding and anticipation of CD4 T-cell epitopes. Currently, 88 and 50 different MHCI and MHCII molecules, respectively, can be targeted for peptide binding predictions in RANKPEP. Because appropriate processing of antigenic peptides must occur prior to major histocompatibility complex (MHC) binding, cleavage site prediction methods are important adjuncts for T-cell epitope discovery. Given that the C-terminus of most MHCI-restricted epitopes results from proteasomal cleavage, we have modeled the cleavage site from known MHCI-restricted epitopes using statistical language models. The RANKPEP server now determines whether the Cterminus of any predicted MHCI ligand may result from such proteasomal cleavage. Also implemented is a variability masking function. This feature focuses prediction on conserved rather than highly variable protein segments encoded by infectious genomes, thereby offering identification of invariant T-cell epitopes to thwart mutation as an immune evasion mechanism.

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“…To obtain optimal peptides that should bind in a homogenous register, the HLA-DR Ã 1101 groove, we designed a series of analogues (Table 1) based on the minimal epitopes defined by using the truncated peptides, that contained a single P1 anchor residue and were extended at the amino or the carboxyl termini with Ala residues to improve their binding stability [38][39][40].…”

Section: Resultsmentioning

confidence: 99%

“…In the p58 peptide, we maintained the single putative anchor residue Met 290 and replaced the two additional putative Val 286 and Leu 287 anchor residues with two Ala [39]. The resulting p58AA analogue was tested for its ability to form functional HLA-DR Ã 1101 tetramers.…”

Section: Resultsmentioning

confidence: 99%

“…3A, two different p57/58-specific T-cell clones, but not an irrelevant T-cell line, were stained by HLA-DR Ã 1101 tetramers loaded with p57/58C3AL peptide. Consistent with published data [8][9][10], the tetramers did not stain the two T-cell clones with the same intensity, in agreement with the different TCR avidity exhibited by the two T-cell clones for the p57/58 peptide (data not shown); 6.22, the T-cell clone with a higher avidity of recognition was stained more brightly by the HLA-DR Ã 1101 loaded with the p57/58C3AL peptide than clone 2E5.53.HLA-DR*1101 tetramers loaded with anchor-tailored p58 peptide stain MAGE-A3-specific CD4 1 T-cell clonesIn the p58 peptide, we maintained the single putative anchor residue Met 290 and replaced the two additional putative Val 286 and Leu 287 anchor residues with two Ala [39]. The resulting p58AA analogue was tested for its ability to form functional HLA-DR Ã 1101 tetramers.…”

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confidence: 99%

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The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

et al. 2010

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Detection of CD4 1 T cells specific for tumor-associated antigens is critical to investigate the spontaneous tumor immunosurveillance and to monitor immunotherapy protocols in patients. We investigated the ability of HLA-DR*1101 multimers to detect CD4 1 T cells specific for three highly promiscuous MAGE-A3 derived peptides: (p39), MAGE-A3 281-295 (p57) and MAGE-A3 286-300 (p58). Tetramers stained specific CD4 1 T cells only when loaded with p39, although all peptides activated the specific T cells when presented by plasticbound HLA-DR*1101 monomers. This suggested that tetramer staining ability was determined by the mode rather than the affinity of peptide binding to HLA-DR*1101. We hypothesized that peptides should bear a single P1 anchor residue to bind all arms of the multimer in a homogeneous register to generate peptide-HLA-DR conformers with maximal avidity. Bioinformatics analysis indicated that p39 contained one putative P1 anchor residue, whereas the other two peptides contained multiple ones. Designing p57 and p58 analogues containing a single anchor residue generated HLA-DR*1101 tetramers that stained specific CD4 1 T cells. Producing HLA-DR*1101 monomers linked with the optimized MAGE-A3 analogues, but not with the original epitopes, further improved tetramer efficiency. Optimization of CD4 1 T-cell epitope-binding registers is thus critical to generate functional HLA-DR tetramers.Key words: Anchor residues . HLA-DR Ã 1101 . MAGE-A3 . MHC tetramers . Tumor antigens Supporting Information available online IntroductionAnimal studies have clearly shown the critical role for CD4 1 T cells in anti-tumor immune response; nevertheless, little is known as yet about spontaneous tumor-specific CD4 1 T-cell responses in patients [1,2]. This knowledge would be instrumental to the definition of the mechanisms underlying tumor immunosurveillance and, possibly, tumor escape, as well as for the correct design of optimal vaccination strategies.CD4 1 T-cell responses specific for tumor associated antigens (TAA) can be investigated at the single cell level by using soluble [3][4][5][6]. The identification of primary antigen-specific CD4 1 T cells by peptide-pulsed MHC class II tetramers seems, however, less straightforward than that of CD8 1 T cells by peptide-loaded MHC class I tetramers [7,8]. Several biological and structural characteristics of the CD4 1 T-cell response that differ from those displayed by the CD8 1 one seem to affect the capacity of MHC class II tetramers to optimally stain specific CD4 1 T cells ex vivo: (i) the lower frequency of peptide-specific CD4 1 T cells, (ii) their apparent lower affinity for the peptide-MHC class II complexes [9][10][11][12][13], and (iii) the requirement for an activation-induced TCR reorganization to bind with sufficient avidity cognate peptide-MHC class II tetramers [12,14,15].Furthermore, the open structure of the MHC class II molecules allows peptides as long as 20 aa to extend out of the binding groove at both ends [16][17][18]. It is thus possible that a peptide,...

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Recognition of core and flanking amino acids of MHC class II-bound peptides by the T cell receptor

Cited by 62 publications

References 39 publications

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Enhancement to the RANKPEP resource for the prediction of peptide binding to MHC molecules using profiles

The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

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Recognition of core and flanking amino acids of MHC class II-bound peptides by the T cell receptor

Cited by 62 publications

References 39 publications

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Enhancement to the RANKPEP resource for the prediction of peptide binding to MHC molecules using profiles

The CD4+ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

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The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides