Insertion of the Dibasic Motif in the Flanking Region of a Cryptic Self-Determinant Leads to Activation of the Epitope-Specific T Cells

Zhu, Hui; Liu, Kechang; Černý, Jan; Imoto, Taiji; Moudgil, Kamal D.

doi:10.4049/jimmunol.175.4.2252

Cited by 16 publications

(20 citation statements)

References 59 publications

(73 reference statements)

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“…First, the finding that DM-negative APC are active at presentation of the cryptic peptides shows that the cryptic epitopes are neither overproteolyzed nor inadequately released during endosomal processing. This finding argued against differential proteolysis of cryptic vs. immunodominant peptides-one of the common explanations for crypticity in immune responses [2,21,22,[44][45][46][47]. Secondly, all immunodominant peptides behaved similarly, and were enhanced by DM while the cryptic epitopes behaved similarly and were antagonized by DM.…”

Section: A Peptide-intrinsic View Of Immunodominance In Cd4 T Cell Rementioning

confidence: 79%

Understanding the focused CD4 T cell response to antigen and pathogenic organisms

Weaver

Sant

2009

Immunol Res

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Immunodominance is a term that reflects the final, very limited peptide specificity of T cells that are elicited during an immune response. Recent experiments in our laboratory compel us to propose a new paradigm for the control of immunodominance in CD4 T cell responses, stating that immunodominance is peptide-intrinsic and is dictated by the off-rate of peptides from MHC class II molecules. Our studies have revealed that persistence of peptide:class II complexes both predicts and controls CD4 T cell immunodominance and that this parameter can be rationally manipulated to either promote or eliminate immune responses. Mechanistically, we have determined that DM editing in APC is a key event that is influenced by the kinetic stability of class II:peptide complexes and that differential persistence of complexes also impacts the expansion phase of the immune response. These studies have important implications for rational vaccine design and for understanding the immunological mechanisms that limit the specificity of CD4 T cell responses.

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Section: A Peptide-intrinsic View Of Immunodominance In Cd4 T Cell Rementioning

confidence: 79%

Understanding the focused CD4 T cell response to antigen and pathogenic organisms

Weaver

Sant

2009

Immunol Res

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“…2), with the difference between SLSDL and LEQLE being the most pronounced. This is yet another example of the influences that flanking sequences can impose upon the MHC class I presentation of epitopes (52)(53)(54)(55)(56). Presumably, the enzymes responsible for removing the N-terminal sequences are more active against LEQLE than the SLSDL sequence.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Role of Bleomycin Hydrolase in Antigen Presentation and the Generation of CD8 T Cell Responses

Towne

York

Watkin

et al. 2007

The Journal of Immunology

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Long oligopeptides (>10 residues) are generated during the catabolism of cellular proteins in the cytosol. To be presented to T cells, such peptides must be trimmed by aminopeptidases to the proper size (typically 8–10 residues) to stably bind to MHC class I molecules. Aminopeptidases also destroy epitopes by trimming them to even shorter lengths. Bleomycin hydrolase (BH) is a cytosolic aminopeptidase that has been suggested to play a key role in generating MHC class I-presented peptides. We show that BH-deficient cells from mice are unimpaired in their ability to present epitopes from N-extended precursors or whole Ags and express normal levels of MHC class I molecules. Similarly, BH-deficient mice develop normal CD8+ T cell responses to eight epitopes from three different viruses in vivo. Therefore, BH by itself is not essential for the generation or destruction of MHC class I peptides. In contrast, when BH−/− mice are crossed to mice lacking another cytosolic aminopeptidase, leucine aminopeptidase, the resulting BH−/−leucine aminopeptidase−/− progeny show a selective increase in CD8+ T cell responses to the gp276 epitope from lymphocytic choriomeningitis virus, whereas the ability to present and respond to several other epitopes is unchanged. Therefore, BH does influence presentation of some Ags, although its role is largely redundant with other aminopeptidases.

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“…It was proposed that self-tolerance might be infringed in autoimmunity by the activation of T cells directed against cryptic self-determinants [15], [16]: well-processed and -presented antigenic determinants are immunodominant, while poorly processed/presented ones curtail the activation of specific T cells and are thus cryptic. Then, certain conditions (e.g., addition of a cleavage site [17] or of inflammatory mediators [18]) can help circumvent self tolerance and thereby lead to autoimmunity. Viral or bacterial infections have also been suspected as triggering factors for autoimmune disorders, possibly through molecular mimicry and/or bystander activation of autoreactive cells.…”

Section: Introductionmentioning

confidence: 99%

Recognition of HIV-1 Peptides by Host CTL Is Related to HIV-1 Similarity to Human Proteins

et al. 2007

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BackgroundWhile human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocytes preferentially target specific regions of the viral proteome, HIV-1 features that contribute to immune recognition are not well understood. One hypothesis is that similarities between HIV and human proteins influence the host immune response, i.e., resemblance between viral and host peptides could preclude reactivity against certain HIV epitopes.Methodology/Principal FindingsWe analyzed the extent of similarity between HIV-1 and the human proteome. Proteins from the HIV-1 B consensus sequence from 2001 were dissected into overlapping k-mers, which were then probed against a non-redundant database of the human proteome in order to identify segments of high similarity. We tested the relationship between HIV-1 similarity to host encoded peptides and immune recognition in HIV-infected individuals, and found that HIV immunogenicity could be partially modulated by the sequence similarity to the host proteome. ELISpot responses to peptides spanning the entire viral proteome evaluated in 314 individuals showed a trend indicating an inverse relationship between the similarity to the host proteome and the frequency of recognition. In addition, analysis of responses by a group of 30 HIV-infected individuals against 944 overlapping peptides representing a broad range of individual HIV-1B Nef variants, affirmed that the degree of similarity to the host was significantly lower for peptides with reactive epitopes than for those that were not recognized.Conclusions/SignificanceOur results suggest that antigenic motifs that are scarcely represented in human proteins might represent more immunogenic CTL targets not selected against in the host. This observation could provide guidance in the design of more effective HIV immunogens, as sequences devoid of host-like features might afford superior immune reactivity.

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Insertion of the Dibasic Motif in the Flanking Region of a Cryptic Self-Determinant Leads to Activation of the Epitope-Specific T Cells

Cited by 16 publications

References 59 publications

Understanding the focused CD4 T cell response to antigen and pathogenic organisms

Understanding the focused CD4 T cell response to antigen and pathogenic organisms

Analysis of the Role of Bleomycin Hydrolase in Antigen Presentation and the Generation of CD8 T Cell Responses

Recognition of HIV-1 Peptides by Host CTL Is Related to HIV-1 Similarity to Human Proteins

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