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Chapter 5 : The Relationship of T-Cell Epitopes and Allergen Structure

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Abstract:

This chapter addresses the relationship of the CD4+ helper T-cell epitope immunodominance to pathways of allergen-antigen processing, as they are directed by protein three-dimensional structures. Allergy is recognized as a failure of immune tolerance by CD4+ T cells. The organization of sections in this chapter is inspired by the steps in the development of immune tolerance and allergy. Several sections deal with general features of the process: a discussion of the cells that process and present food allergens; a discussion of the lysosomal enzymes that process allergens; a brief summary of evidence that proteolytic processing follows pathways that could depend on molecular and cellular contexts; evidence that antigen processing and peptide loading occur in the same compartment, where the two mechanisms may interact; the idea that tolerance and immunity represent different outcomes of the same mechanism of antigen processing; and a summary of the most direct evidence that the antigen-allergen structure has an influence on epitope dominance, including a discussion of the nature of structural data and how it is used. A section discusses the relationship of structure and epitope dominance for human immunodeficiency virus (HIV) gp120 and several food allergens: chicken lysozyme, chicken ovalbumin, bovine ß-lactoglobulin (BLG), and the birch tree aeroallergen Bet v 1. The final section discusses the implications of the relationship of structure to dominance on the development of allergy, evolution of the immune system, and allergy immunotherapy.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5

Key Concept Ranking

T Cell Epitope
0.6118526
Immune Response
0.55335766
Amino Acids
0.47129917
T Helper Cells
0.45532104
0.6118526
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Figures

Image of Figure 1.
Figure 1.

Schematic diagram indicating the steps involved in the development of regulatory, Th2, or Th1 cells, highlighting the idea that antigen processing and peptide presentation are essentially the same for presentation to all types of T cells. The developmental decision between cell types is made by DCs, which receive signals from preexisting T cells, epithelial cells, and pathogen-associated molecular patterns.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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Image of Figure 2.
Figure 2.

Model of antigen-allergen processing and presentation of dominant CD4 T-cell epitopes. Local structural breathing occurs in unstable loops between stable elements of secondary or tertiary structures. Unstable loops contain preferred sites for proteolytic cleavage because these segments of polypeptide most easily conform to protease-active sites. During or after cleavage, segments adjacent to cleavage sites become destabilized and bind to MHC-II antigen-presenting proteins. Further proteolytic trimming reduces the MHC-bound peptide to the typical size of 12 to 15 residues.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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Image of Figure 3.
Figure 3.

Structure and epitope dominance in HIV envelope glycoprotein gp120. (A) Ribbon diagram of the crystal structure of core gp120, showing the dominant epitope identified in CBA and BALB/c mice (highlighted in gray). (B) Profile of crystallographic B factors for nitrogen atoms in core gp120. (C) Epitope dominance determined by proliferation of splenocytes from gp120-immunized CBA mice, with the dominant epitope highlighted in gray. (D) Epitope dominance determined by proliferation of splenocytes from gp120-immunized BALB/c mice, with the dominant epitope highlighted in gray. (E) Epitope dominance determined by counting IFN-γ immunospots formed by freshly prepared T cells from a single HIV donor. The single most immunogenic sequence of gp120 is the same in both CBA and BALB/c mice, and it corresponds to an epitope in the HIV donor. Since this sequence is flanked by peaks in the B-factor profile, it is likely to be processed and presented most efficiently. Data sources were as follows: for crystal structure and B factors, Protein Data Bank (PDB) accession no. 1GC1; epitopes in mice were from ; and epitopes in humans were from . Data processing was as follows. Experimental B factors were not available for the hypervariable loops, either because these segments were removed from the protein prior to crystallization or because their disorder prevented electron density from being observed. For these segments, B factors were arbitrarily assigned a value of 100. Epitope frequencies and ELISPOT numbers were assigned to individual residues on the basis of the residue’s presence in a peptide that stimulated proliferation or cytokine expression. A given residue was counted twice if it was present in two consecutive (overlapping) peptides that stimulated a response.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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Image of Figure 4.
Figure 4.

Structure and epitope dominance in HEL. (A) Ribbon diagram of the NMR structure, showing large and small stable subdomains identified in the COREX/BEST residue stability profile (highlighted in black and gray, respectively). (B) Ribbon diagram showing the dominant epitopes in C3H and BALB/c mice (highlighted in black and gray, respectively). (C) Diagram of disulfide bond connectivity. (D) Three profiles of flexibility-stability: nitrogen atom RMSDs from NMR (thin line), nitrogen atom crystallographic B factors (medium line), and COREX/BEST residue stability profile (thick line). (E) Profile of stimulation index for proliferation of splenocytes from immunized C3H mice. (F) Profile of stimulation index for proliferation of splenocytes from immunized BALB/c mice. Arrows and dashed lines indicate peaks in the flexibility profile that may correspond to proteolytic cleavage sites. The dominant epitope in C3H mice lies between two peaks of flexibility and on the carboxy-terminal flank of a stable subdomain. Likewise, the dominant epitope in BALB/c mice lies between a peak of flexibility and the carboxy terminus and on the carboxy-terminal flank of a stable subdomain. Data sources are as follows: NMR structure and RMSDs, PDB accession no. 1E8L; B factors, PDB accession no. 2LYM; epitopes in C3H mice were from ; and epitopes in BALB/c mice were from . For data processing, RMSDs were calculated by the facility in MOLMOL ( ) for the mean of 50 NMR structures reported in the PDB file. Residue stabilities were calculated with COREX/BEST with the minimized average NMR structure (PDB accession no. 1GXV) and default values for all parameters, with an entropy weighting factor of 0.95.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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Image of Figure 5.
Figure 5.

Structure and epitope dominance in mouse lysozyme M. (A) Ribbon diagram of the NMR structure, showing the dominant epitope in C3H mice (highlighted in gray). (B) Profiles of nitrogen atom RMSD from NMR (thin line), and COREX/BEST residue stability profile (thick line). (C) Profile of stimulation index for proliferation of splenocytes from immunized C3H mice. Lysozyme M does not have a strong response at residues 51 to 62, which was dominant for HEL in the C3H mice. The dominant epitope for lysozyme M in C3H mice corresponds to the dominant epitope for HEL in BALB/c mice. The sequence of residues 52 to 61 is nearly identical in HEL and lysozyme M; thus, the lack of response in lysozyme M probably is not due to peptide selectivity by the MHC-II protein. Profiles of flexibility-stability in HEL and lysozyme M are similar; thus, the pathways of proteolytic processing for the two proteins are likely to yield 52-61 in comparable abundance. The absence of response to 52-61 could be due to tolerance of this highly conserved segment in other mouse lysozymes, including lysozyme P. Data sources are as follows: for NMR structure and RMSDs, PDB accession no. 1IVM; epitopes in C3H mice were from . Data processing was as follows: RMSDs were calculated by the facility in MOLMOL ( ) for the mean of 20 structures reported in the PDB file. Residue stabilities were calculated using COREX/BEST with model 1 of the NMR structure (PDB accession no. 1IVM) and default values for all parameters, with an entropy weighting factor of 0.90.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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Image of Figure 6.
Figure 6.

Structure and epitope dominance in chicken ovalbumin. (A) Ribbon diagram of the crystal structure, showing one of the dominant epitopes in allergic humans (highlighted in gray). (B) Ribbon diagram showing the dominant epitope in immunized mice (highlighted in gray). (C) Ribbon diagram showing two stable subdomains that may promote the dominance of epitopes in segments 1 to 49 and 204 to 251 (highlighted in gray and black, respectively). (D) Profiles of flexibility-stability, indicated by crystallographic B factor (thin line) and COREX/BEST residue stability (thick line). (E) Epitope dominance determined by frequency of recognition by hybridomas generated from an immunized mouse. (F) Epitope dominance determined by frequency of recognition by T-cell lines generated from allergic humans. Arrows and dashed lines indicate peaks in the flexibility profile that may correspond to proteolytic cleavage sites. The dominant epitope in mice lies between flexible sites and on the carboxy-terminal flank of a stable subdomain. One of two dominant epitopes associated with allergy lies on the amino-terminal flank of the same stable subdomain that contains the dominant mouse epitope. The other dominant epitope associated with allergy lies in a stable subdomain between the amino terminus and a protease-sensitive site. Data sources are as follows: crystal structure and B factors, PDB accession no. 1UHG; epitopes in mice were from and ; epitopes in humans were from and . Data processing was as follows: residue stabilities were calculated using COREX/BEST with the crystal structure (PDB accession no. 1UHG) and default values for all parameters, except with a window size of 27, temperature of 37°C, and an entropy weighting factor of 0.98.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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Image of Figure 7.
Figure 7.

Structure and epitope dominance in BLG. (A) Ribbon diagram of the crystal structure, showing a structurally unstable segment that is immunodominant in BALB/c mice (highlighted in black). (B) Ribbon diagram of the crystal structure, showing the dominant epitope in allergic humans (highlighted in gray). (C) Ribbon diagram as in B rotated 90° about the vertical axis. (D) Profiles of flexibility-stability, indicated by nitrogen atom crystallographic B factor (thin line) and COREX/BEST residue stability (thick line). (E) Epitope dominance determined by frequency of occurrence in determinant cores observed with C57BL/6 mice. (F) Epitope dominance determined by frequency of occurrence in determinant cores observed with C3H/HeN mice. (G) Epitope dominance determined by frequency of occurrence in determinant cores observed with BALB/c mice. (H) Epitope dominance determined by frequency of recognition by T-cell lines generated from allergic humans. Arrows and dashed lines indicate peaks in the B-factor profile that may correspond to proteolytic cleavage sites. Mouse determinant cores tend to lie between peaks of flexibility and are associated with stable subdomains, except in BALB/c mice, where the epitope with strongest proliferative responses (highlighted in black) was associated with an unstable subdomain. The dominant epitope associated with human allergy (highlighted in gray) lies between the amino terminus and a protease-sensitive site. Data sources are as follows: crystal structure and B factors, PDB accession no. 1BSY; mouse determinant cores were from ; epitopes in humans were from . Data processing was as follows: residue stabilities were calculated using COREX/BEST with the crystal structure (PDB accession no. 1BSY) and default values for all parameters, except with an entropy-weighting factor of 0.95.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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Image of Figure 8.
Figure 8.

Structure and epitope dominance in birch pollen allergen Bet v 1. (A) Ribbon diagram of the crystal structure, showing two dominant epitopes in allergic humans (highlighted in black or gray). (B) Ribbon diagram showing a structurally unstable region that is poorly immunogenic. (C) Profiles of flexibility-stability for Bet v 1 variant L, indicated by crystallographic B factor (thin line) and COREX/BEST residue-stability (thick line). (D) Epitope dominance in Bet v 1 determined by frequency of recognition by T-cell lines generated from birch-allergic humans. (E) Epitope dominance in Api g 1 determined by frequency of recognition by T-cell lines generated from celery-allergic humans. (F) Profiles of flexibility for Bet v 1 variant A, indicated by nitrogen atom crystallographic B factor (thin line) and nitrogen atom RMSD from NMR (thick line). Arrows and dashed lines indicate peaks in flexibility profile that may correspond to proteolytic cleavage sites. Dominant epitopes associated with allergy lie between flexible sites and are excluded from the structurally unstable region. Data sources are as follows: crystal structure and B factors (A), PDB accession no. 1FM4; B factors (F), PDB accession no. 1BV1; RMSDs, PDB accession no. 1BTV; Bet v 1 epitopes were from ; Api g 1 epitopes were from . Data processing is as follows: residue stabilities were calculated using COREX/BEST with the crystal structure (PDB accession no. 1BTV) and default values for all parameters, except with an entropy weighting factor of 0.90.

Citation: Landry S. 2006. The Relationship of T-Cell Epitopes and Allergen Structure, p 123-159. In Maleki S, Burks A, Helm R (ed), Food Allergy. ASM Press, Washington, DC. doi: 10.1128/9781555815721.ch5
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