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Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT.

ABSTRACT: Peptide antigen presentation by major histocompatibility complex (MHC) class I proteins initiates CD8+ T cell-mediated immunity against pathogens and cancers. MHC I molecules typically bind peptides with 9 amino acids in length with both ends tucked inside the major A and F binding pockets. It has been known for a while that longer peptides can also bind by either bulging out of the groove in the middle of the peptide or by binding in a zigzag fashion inside the groove. In a recent study, we identified an alternative binding conformation of naturally occurring peptides from Toxoplasma gondii bound by HLA-A*02:01. These peptides were extended at the C terminus (P?) and contained charged amino acids not more than 3 residues after the anchor amino acid at P?, which enabled them to open the F pocket and expose their C-terminal extension into the solvent. Here, we show that the mechanism of F pocket opening is dictated by the charge of the first charged amino acid found within the extension. Although positively charged amino acids result in the Tyr-84 swing, amino acids that are negatively charged induce a not previously described Lys-146 lift. Furthermore, we demonstrate that the peptides with alternative binding modes have properties that fit very poorly to the conventional MHC class I pathway and suggest they are presented via alternative means, potentially including cross-presentation via the MHC class II pathway.

SUBMITTER: Remesh SG

PROVIDER: S-EPMC5392673 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT.

Remesh Soumya G SG Andreatta Massimo M Ying Ge G Kaever Thomas T Nielsen Morten M McMurtrey Curtis C Hildebrand William W Peters Bjoern B Zajonc Dirk M DM

The Journal of biological chemistry 20170208 13

Peptide antigen presentation by major histocompatibility complex (MHC) class I proteins initiates CD8<sup>+</sup> T cell-mediated immunity against pathogens and cancers. MHC I molecules typically bind peptides with 9 amino acids in length with both ends tucked inside the major A and F binding pockets. It has been known for a while that longer peptides can also bind by either bulging out of the groove in the middle of the peptide or by binding in a zigzag fashion inside the groove. In a recent st ...[more]

PMID: 28179428

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

Project description:BackgroundAn inefficient immune response against Epstein-Barr virus (EBV) infection is related to the pathogenesis of a subgroup of classical Hodgkin lymphomas (cHL). Some EBV immune-evasion mechanisms target HLA presentation, including the non-classical HLA-E molecule. HLA-E can be recognized by T cells via the TCR, and it also regulates natural killer (NK) cell signaling through the inhibitory CD94/NKG2A receptor. Some evidences indicate that EBV-infected B-cells promote the proliferation of NK subsets bearing CD94/NKG2A, suggesting a relevant function of these cells in EBV control. Variations in CD94/NKG2A-HLA-E interactions could affect NK cell-mediated immunity and, consequently, play a role in EBV-driven transformation and lymphomagenesis. The two most common HLA-E alleles, E*01:01 and E*01:03, differ by a single amino acid change that modifies the molecule function. We hypothesized that the functional differences in these variants might participate in the pathogenicity of EBV.AimWe studied two series of cHL patients, both with EBV-positive and-negative cases, and a cohort of unrelated controls, to assess the impact of HLA-E variants on EBV-related cHL susceptibility.ResultsWe found that the genotypes with at least one copy of E*01:01 (i.e., E*01:01 homozygous and heterozygous) were underrepresented among cHL patients from both series compared to controls (72.6% and 71.6% vs 83%, p = 0.001). After stratification by EBV status, we found low rates of E*01:01-carriers mainly among EBV-positive cases (67.6%). These reduced frequencies are seen independently of other factors such as age, gender, HLA-A*01 and HLA-A*02, HLA alleles positively and negatively associated with the disease (adjusted OR = 0.4, p = 0.001). Furthermore, alleles from both HLA loci exert a cumulative effect on EBV-associated cHL susceptibility.ConclusionsThese results indicate that E*01:01 is a novel protective genetic factor in EBV-associated cHL and support a role for HLA-E recognition on the control of EBV infection and lymphomagenesis.

Dataset Information

Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT.

Publications

Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT.

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