The Relation Between Major Histocompatibility Complex (MHC) Restriction and the Capacity of Ia to Bind Immunogenic Peptides

Buus, Søren; Sette, Alessandro; Colón, S M; Miles, Craig; Grey, Howard M.

doi:10.1126/science.2435001

Cited by 652 publications

(291 citation statements)

References 35 publications

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“…Also, the association pattern of peptides to different allele variants of murine Ia is a reflection of the MHC restriction of the immune response [3,4]. Several workers have attempted to unravel the relevant struc-tural requirements of TD h peptides to interact with murine [5][6][7] or human [8 -14] class II molecules.…”

Section: Determinants Recognized By T-helper Cellsmentioning

confidence: 99%

Specific and general HLA-DR binding motifs: comparison of algorithms

et al. 2000

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Using panels of peptides well characterized for their ability to bind to HLA DR1, DRB1*1101, or DRB1*0401 molecules, algorithms were deduced to predict binding to these molecules. These algorithms consist of blocks of 8 amino acids containing an amino acid anchor (Tyr, Phe, Trp, Leu, Ile, or Val) at position i and different amino acid combinations at positions i؉2 to i؉7 depending on the class II molecule. The sensitivity (% of correctly predicted binder peptides) and specificity (% of correctly predicted non-binder peptides) of these algorithms, were tested against different independent panels of peptides and compared to other algorithms reported in the literature. Similarly, using a panel of 232 peptides able to bind to one or more HLA molecules as well as 43 non-binder peptides, we deduced a general motif for the prediction of binding to HLA-DR molecules. The sensitivity and specificity of this general motif was dependent on the threshold score used for the predictions. For a score of 0.1, the sensitivity and specificity were 84.7% and 69.8%, respectively. This motif was validated against several panels of binder and non-binder peptides reported in the literature, as well as against 35, 15-mer peptides from hepatitis C virus core protein, that were synthesized and tested in a binding assay against a panel of 19 HLA-DR molecules. The sensitivities and specificities against these panels of peptides were similar to those attained against the panels used to deduce the algorithm. These results show that comparison of binder and non-binder peptides, as well as correcting for the relative abundance of amino acids in proteins, is a useful approach to deduce performing algorithms to predict binding to HLA molecules.

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Section: Determinants Recognized By T-helper Cellsmentioning

confidence: 99%

Specific and general HLA-DR binding motifs: comparison of algorithms

et al. 2000

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“…T cells do not recognize native protein antigens, unless previously denatured or partially degraded, and subsequently displayed in association with MHC class II (Ia) molecules by APC. The pattern of peptide association with various allelic variants of Ia reflects the pattern of MHC restriction of the immune response [11,12]. The structural requirements for their interactions have been subjected to an intense investigation.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A

López-Moratalla

et al. 1994

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Peptides from 10 to 22 amino acids containing sequences encompassed by Staphylococcus aureus protein A were synthesized. Some of these peptides, when present in cultures of lymphomononuclear cells from healthy donors or from cancer patients (melanoma, breast carcinoma, non-Hodgkin lymphoma and renal cell carcinoma) promoted: (i) changes in the phenotype of the lymphomononuclear population, (ii) stimulation of monocytes (release of IL-1 and TNF-a), and (iii) an increase in cytotoxicity against K562, Daudi and HT-29 cells. Isolated monocytes responded also to those peptides with a release of IL-1 and TNFa and an increase of cytotoxicity against HT-29 cells. It was found that the active peptides had the following structural pattern: a length of at least 15 amino-acid residues with a proline at position 6, valine, leucine, isoleucine, glycine, alanine or lysine at position 2, and glutamic or aspartic acid at position 11. Replacement of Pro at position 6 with any other residue turned the peptide inactive. Replacement of residues at positions 2 and 11 with amino-acid residues other than those required for activity resulted in compounds with a marked decrease in the immunomodulating properties described, or lacking these properties altogether.

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“…Because of their small size, the CD4 1 T-cell response specific for Tat and Vpr proteins is expected to largely depend on the HLA molecules. As illustrated by pioneering studies on the genetic control of the immune response in mice [23] and humans [24], small proteins lead to high and low responders because of the presence or absence of peptide sequences able to be presented to T cells by the MHC class II molecules [25]. In humans, a high frequency of responders to a candidate vaccine is a requisite, but the underlying mechanisms of this process are poorly understood.…”

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confidence: 99%

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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The Relation Between Major Histocompatibility Complex (MHC) Restriction and the Capacity of Ia to Bind Immunogenic Peptides

Cited by 652 publications

References 35 publications

Specific and general HLA-DR binding motifs: comparison of algorithms

Specific and general HLA-DR binding motifs: comparison of algorithms

Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A

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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The Relation Between Major Histocompatibility Complex (MHC) Restriction and the Capacity of Ia to Bind Immunogenic Peptides

Cited by 652 publications

References 35 publications

Specific and general HLA-DR binding motifs: comparison of algorithms

Specific and general HLA-DR binding motifs: comparison of algorithms

Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A

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

Contact Info

Product

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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