T-Cell Epitope Prediction: Rescaling Can Mask Biological Variation between MHC Molecules

MacNamara, Aidan; Kadolsky, Ulrich D.; Bangham, Charles R. M.; Asquith, Becca

doi:10.4016/10738.01

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…Once the peptide–MHC predictions are made, one needs to define a threshold that separates predicted binders from nonbinders. Recently, the choice of thresholds has been discussed extensively 43. One possibility is to assume a fixed threshold holds for all MHC molecules, e.g.…”

Section: Methodsmentioning

confidence: 99%

MHC class I molecules exploit the low G+C content of pathogen genomes for enhanced presentation

2010

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Distinguishing self from nonself and pathogenic from nonpathogenic is a fundamental challenge to the immune system but whether adaptive immune systems use pathogenspecific signatures to achieve this is largely unknown. By investigating the presentation of large sets of viruses and bacteria on MHC class I molecules, we analyze whether MHC-I molecules have a preference for pathogen-derived peptides. The fraction of potential MHC-I binders in different organisms can vary up to eight-fold. We find that this variation can be largely explained by G1C content differences of the organisms, which are reflected in amino acid frequencies. A significant majority of HLA-A, but not HLA-B, molecules has a preference for peptides derived from organisms with a low G1C content. Interestingly, a low G1C content seems to be a universal signature for pathogenicity. Finally, we find the same preferences in chimpanzee and rhesus macaque MHC-I molecules. These results demonstrate that despite the fast evolution of MHC-I alleles and their extreme polymorphism and diversity in peptide-binding preferences, MHC-I molecules can acquire a preference to exploit pathogen-specific signatures.Key words: G1C content . HLA alleles . MHC-I presentation . Self/nonself discrimination See accompanying article by Levasseur and Pontarotti Supporting Information available online Introduction MHC class I (MHC-I) presentation of peptides is crucial for the cytotoxic T-cell response. The process of MHC-I presentation involves the cytosolic degradation of proteins by the proteasome, translocation of peptides to the endoplasmatic reticulum by TAP, N-terminal trimming of peptides by aminopeptidases, binding of 8-11 amino acid long peptides to MHC-I molecules to form peptide-MHC-I complexes (pMHC) and pMHC-transport to and from the cell surface [1][2][3][4][5]. T cells recognizing foreign pMHC will become activated and proliferate to seek and destroy other cells presenting the same pMHC. Thus, the presentation of pathogenderived peptides on MHC-I molecules is required to elicit an effective immune response. Self-and pathogen-derived peptides compete for presentation on the same MHC-I molecules. Given the enormous turnover of self-proteins (about 10 6 peptides are generated by the proteasome every second [6]) and limited number of MHC-I molecules ($10 5 ), only a small fraction of all pathogen-derived peptides will be presented on the cell surface [7]. Another requirement for an effective immune response is that pathogen-derived pMHC are different from selfderived pMHC, since most self-reactive T-cells are tolerized during negative selection [8]. MHC-I molecules that prefer to bind pathogen-specific peptides will be able to fulfill these Eur. J. Immunol. 2010. 40: 2699-2709 DOI 10.1002 Antigen processing 2699 requirements best and provide a selective advantage. However, such a preference to enhance the MHC-I presentation of pathogen-specific peptides has thus far not been described. HLA molecules are encoded by the most polymorphic genes in the human population...

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Section: Methodsmentioning

confidence: 99%

MHC class I molecules exploit the low G+C content of pathogen genomes for enhanced presentation

2010

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“…As an alternative approach, MacNamara et al conducted a systematic study that tested the capacity of an individual's HLA alleles to bind HTLV-1 peptides and asked whether this metric correlated with the proviral load and the “risk” (i.e., relative prevalence) of HAM/TSP. They used experimentally validated epitope prediction software [ 41 ] which predicted the affinity of binding of peptides derived from the HTLV-1 genome to HLA-A and -B alleles in a cohort of 202 ACs and 230 patients with HAM/TSP [ 42 ]. They found that the known protective alleles A*0201 and C*0801 bound peptides from HBZ with significantly higher affinity than alleles which were associated with disease progression (B*5401).…”

Section: Hla Class 1 and The Immune Response To Htlv-1mentioning

confidence: 99%

Is There a Role for HTLV-1-Specific CTL in Adult T-Cell Leukemia/Lymphoma?

Rowan

Bangham

2012

Leukemia Research and Treatment

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ATLL is an aggressive malignancy of T cells that affects about 5% of individuals infected with HTLV-1. The precise mechanism of oncogenesis is not known, but there is evidence that two regulatory viral proteins, Tax and HBZ, are involved. A high set point proviral load is associated with development of ATLL or a chronic inflammatory condition, HAM/TSP. Several lines of evidence, including HLA class 1 association studies and in vitro killing assays, indicate that cytotoxic T lymphocytes are instrumental in determining this proviral load set point. Prior studies have focused chiefly on the CTL response to the immunodominant Tax protein: efficient lysis of Tax-expressing cells inversely correlates with proviral load in nonmalignant infection. However, a recent study showed that strong binding of peptides from HBZ, but not Tax, to HLA class 1 molecules was associated with a low proviral load and a reduced risk of developing HAM/TSP, indicating an important role for HBZ-specific CTL in determining infection outcome. In comparison with nonmalignant infection, HTLV-1-specific CTLs in ATLL patients are reduced in frequency and functionally deficient. Here we discuss the nature of protective CTL responses in nonmalignant HTLV-1 infection and explore the potential of CTLs to protect against ATLL.

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“…It should be noted that computer-based epitope prediction capabilities are constantly extended: appearance of new information on mapped B-and T-epitopes results in the more exact specification of corresponding patterns and, consequently, in increased effectiveness of corresponding program products. New, more convenient interfaces are developed for servers containing epitope databases and prediction tools; the development of integrated servers allows to search for possible B-and T-epitopes and combine them into putative immunogenic constructions at one place (Sieker et al, 2009;Wiwanitkit, 2009;MacNamara et al, 2009;Lin et al, 2008;Perry et al, 2008;Roggen, 2006;Tian et al, 2009;Schuler et al, 2007).…”

Section: Selection Of Antigenic Determinants For Immunogenic Constructsmentioning

confidence: 99%

Insight and Control of Infectious Disease in Global Scenario

Roy¹

2012

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T-Cell Epitope Prediction: Rescaling Can Mask Biological Variation between MHC Molecules

Cited by 6 publications

References 22 publications

MHC class I molecules exploit the low G+C content of pathogen genomes for enhanced presentation

MHC class I molecules exploit the low G+C content of pathogen genomes for enhanced presentation

Is There a Role for HTLV-1-Specific CTL in Adult T-Cell Leukemia/Lymphoma?

Insight and Control of Infectious Disease in Global Scenario

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