Antigen three-dimensional structure guides the processing and presentation of helper T-cell epitopes

Carmicle, Stephanie; Steede, N. Kalaya; Landry, Samuel J.

doi:10.1016/j.molimm.2006.06.014

Cited by 38 publications

(39 citation statements)

References 47 publications

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“…Our findings correlate well with previous studies suggesting that CD4 ϩ T-cell epitopes are preferentially associated with structurally stable regions of proteins (25,41). However, given the breadth of responses targeted against different regions of the GP protein, our findings diverge from previous studies, which have shown that immunodominant responses cluster in limited regions of particular antigens (8,10,25,37).…”

Section: Fig 4 Identification Of Cd4supporting

confidence: 85%

Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 ⁺ and CD8 ⁺ T-Cell Responses

Dow

Oseroff

Peters

et al. 2008

J Virol

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Activation of CD4؉ epitopes, four of them also stimulate CD8 ؉ T cells in a statistically significant manner. Furthermore, we assessed these CD4 ؉ T-cell responses during the memory phase of LCMV Armstrong infection and after infection with a chronic strain of LCMV and determined that a subset of the responses could be detected under these different conditions. This is the first example of a broad repertoire of shared epitopes between CD4 ؉ and CD8 ؉ T cells in the context of viral infection. These findings demonstrate that immunodominance is a complex phenomenon in the context of helper responses.

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Section: Fig 4 Identification Of Cd4supporting

confidence: 85%

Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 ⁺ and CD8 ⁺ T-Cell Responses

Dow

Oseroff

Peters

et al. 2008

J Virol

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“…In our work, we have used 3-D structural data (mostly X-ray crystal structures) to correlate immunodominant epitopes with adjacent flexible segments [19,[21][22][23]. We have demonstrated experimentally that reducing the proteolytic sensitivity of a flexible segment reduces the immunogenicity of an adjacent helper T-cell epitope and increases the immunogenicity of other epitopes [23,24]. Our studies have shown that the pattern of helper T-cell epitopes and adjacent flexible loops holds for the structurally stable outer domain of HIV gp120 in BALB/c and CBA mice [25].…”

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confidence: 99%

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

2008

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The development of an effective vaccine against HIV/AIDS has been hampered, in part, by a poor understanding of the rules governing helper T-cell epitope immunodominance. Studies in mice have shown that antigen structure modulates epitope immunodominance by affecting the processing and subsequent presentation of helper T-cell epitopes. Previous epitope mapping studies showed that the immunodominant helper T-cell epitopes in mice immunized with gp120 were found flanking flexible loops of the protein. In this report, we show that helper T-cell epitopes against gp120 in humans infected with HIV are also found flanking flexible loops. Immunodominant epitopes were found to be located primarily in the outer domain, an average of 12 residues C-terminal to flexible loops. In the less immunogenic inner domain, epitopes were found an average of five residues N-terminal to conserved regions of the protein, once again placing the epitopes C-terminal to flexible loops. These results show that antigen structure plays a significant role in the shaping of the helper T-cell response against HIV gp120 in humans. This relationship between antigen structure and helper T-cell epitope immunodominance may prove to be useful in the development of rationally designed vaccines against pathogens such as HIV.Key words: Antigen processing Á Helper T lymphocyte Á HIV envelope protein gp120 Á MHC class II Á Protein structure IntroductionOver the past 25 years, great strides have been made in the area of HIV/AIDS research. Much is now known about the biology and pathogenesis of the virus. In spite of this, HIV/AIDS continues to be a major health problem worldwide. In 2006, there were approximately 4.3 million new HIV cases, 400 000 more cases than in 2004, bringing the global total of people living with HIV to 39.5 million [1]. This number reflects the increase of HIV cases in every region of the world, suggesting that the epidemic is far from declining. In order to reverse this trend, an effective vaccine against HIV must be developed.Studies in humans and non-human primates have shown that the CD8 + cytotoxic T lymphocyte (CTL) response is essential to the control of viremia [2][3][4][5][6]. Neutralizing antibody has also been shown to aid in the maintenance of low viral loads, presumably through the prevention of viral transmission from cell to cell [7][8][9]. CD4 + helper T cells are required for the induction and maintenance of both of these effector mechanisms [10][11][12][13][14][15][16][17][18]. Therefore, the ideal vaccine against HIV must be able to activate these three arms of the immune response in order to confer protection against infection and disease progression. Helper T-cell activation begins when an immature CD4 + T cell encounters an antigen-presenting cell (APC) displaying a peptide bound to an MHC class II molecule (pMHCII). This contact between the CD4 + T cell and the pMHCII complex initiates a signaling cascade that leads to the maturation of the helper T cell. Although every sequence within a protein antigen can poten...

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“…An epitope's structural context has been shown to influence CD4 ϩ T-cell epitope dominance at the level of antigen processing (4,9,14,45,62,65,67,68,73), but a general relationship between structure and immunodominance has not been described. Processing of CD4 ϩ epitopes occurs in a lysosomelike compartment, where there is no evidence for ATP-dependent protein-unfolding mechanisms other than lysosomal acidification (72).…”

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Three-Dimensional Structure Determines the Pattern of CD4⁺T-Cell Epitope Dominance in Influenza Virus Hemagglutinin

Landry

2008

J Virol

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The structural context of a CD4؉ T-cell epitope is known to influence immunodominance at the level of antigen processing, but general rules have not emerged. Dominant epitopes of influenza virus hemagglutinin are found to be localized to the C-terminal flanks of conformationally stable segments identified by low crystallographic B-factors or high COREX residue stabilities. The bias toward C-terminal flanks is distinctive for antigens from the influenza virus. Dominant epitopes in antigens/allergens from other sources also localize to the flanks of stable segments but are found on either N-or C-terminal flanks. Thus, dominance arises from preferential endoproteolytic nicking between stable segments followed by loading of fragment terminal regions into antigen-presenting proteins. This mechanism probably arose in order to direct CD4 ؉ responses onto sequences that are conserved for structure and function. Structure-guided presentation could enhance protection against genetically drifting influenza virus variants but most likely reduces protection against new viral subtypes.

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Antigen three-dimensional structure guides the processing and presentation of helper T-cell epitopes

Cited by 38 publications

References 47 publications

Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 ⁺ and CD8 ⁺ T-Cell Responses

Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 ⁺ and CD8 ⁺ T-Cell Responses

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

Three-Dimensional Structure Determines the Pattern of CD4⁺T-Cell Epitope Dominance in Influenza Virus Hemagglutinin

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Antigen three-dimensional structure guides the processing and presentation of helper T-cell epitopes

Cited by 38 publications

References 47 publications

Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 + and CD8 + T-Cell Responses

Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 + and CD8 + T-Cell Responses

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

Three-Dimensional Structure Determines the Pattern of CD4+T-Cell Epitope Dominance in Influenza Virus Hemagglutinin

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Resources

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Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 ⁺ and CD8 ⁺ T-Cell Responses

Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4 ⁺ and CD8 ⁺ T-Cell Responses

Three-Dimensional Structure Determines the Pattern of CD4⁺T-Cell Epitope Dominance in Influenza Virus Hemagglutinin