Extensive major histocompatibility complex class I binding promiscuity for <i>Mycobacterium tuberculosis</i> TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)‐B*0702 and HLA‐B*0801 alleles in TB10.4 CD8<sup>+</sup> T‐cell responses

Axelsson-Robertson, Rebecca; Weichold, Frank F.; Sizemore, Donata; Wulf, Markus; Skeiky, Yasir A. W.; Sadoff, Jerry; Maeurer, Markus

doi:10.1111/j.1365-2567.2009.03201.x

Cited by 41 publications

(54 citation statements)

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“…These studies suggest that this observation is not limited to RNA viruses. In fact it has even been described for an intracellular bacterial pathogen, Mycobacterium tuberculosis (76, 77). Furthermore, HLA B restricted T cell responses have been described to be of higher magnitude (73) and have been described to influence infectious disease course and outcome.…”

Section: Discussionmentioning

confidence: 99%

Insights into HLA-Restricted T Cell Responses in a Novel Mouse Model of Dengue Virus Infection Point toward New Implications for Vaccine Design

Weiskopf

Yauch

Angelo

et al. 2011

The Journal of Immunology

113

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The frequency of dengue virus (DENV) infection has increased dramatically in the last few decades, and the lack of a vaccine has led to significant morbidity and mortality worldwide. To date, a convenient murine system to study human T cell responses to DENV has not been available. Mice transgenic for human leukocyte antigens (HLA) are widely used to model human immune responses and it has been shown that mouse-passaged DENV is able to replicate to significant levels in IFN-α/βR−/− mice. To cover a wide range of HLA phenotypes, we backcrossed IFN-α/βR−/− mice with HLA A*0201, A*0101, A*1101, B*0702 and DRB1*0101 transgenic mice. A DENV proteome-wide screen identified a total of 42 epitopes across all HLA-transgenic IFN-α/βR−/− strains tested. In contrast only 8 of these elicited responses in the corresponding IFN-α/βR+/+ mice. We were able to identify T cell epitopes from 9 out of the 10 DENV proteins. However, the majority of responses were derived from the highly conserved nonstructural proteins NS3 and NS5. The relevance of this model is further demonstrated by the fact that most of the epitopes identified in our murine system are also recognized by PBMC from DENV exposed human donors, and a dominance of HLA B*0702 restricted responses has been detected in both systems. Our results provide new insights into HLA-restricted T cell responses against DENV, and we herein describe a novel murine model, which allows the investigation of T cell-mediated immune mechanisms relevant to vaccine design.

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Section: Discussionmentioning

confidence: 99%

Insights into HLA-Restricted T Cell Responses in a Novel Mouse Model of Dengue Virus Infection Point toward New Implications for Vaccine Design

Weiskopf

Yauch

Angelo

et al. 2011

The Journal of Immunology

113

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“…These data are best explained by a model in which the T-cell clone recognizes Rv2034 p81–100 and Rv2034 p88–107 via multiple HLA molecules, possibly including HLA-DR2, -DR3 as well as HLA-DQ1 registers, but that the dominant response to the protein is HLA-DR restricted. Such promiscuous peptides, capable of being presented by multiple HLA molecules, have been shown for several mycobacterial proteins [56], including HspX (16 kDa protein) [57], TB10.4 [58] and Hsp65 [59]. In addition, some ( Mtb antigen) studies showed possible presentation of a single epitope, specific for one clone, via both HLA-DR and HLA-DQ [57], [60].…”

Section: Resultsmentioning

confidence: 99%

Clonal Analysis of the T-Cell Response to In Vivo Expressed Mycobacterium tuberculosis Protein Rv2034, Using a CD154 Expression Based T-Cell Cloning Method

et al. 2014

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of death worldwide. A better understanding of the role of CD4+ and CD8+ T cells, which are both important to TB protection, is essential to unravel the mechanisms of protection and to identify the key antigens seen by these T cells. We have recently identified a set of in vivo expressed Mtb genes (IVE-TB) which is expressed during in vivo pulmonary infection in mice, and shown that their encoded antigens are potently recognized by polyclonal T cells from tuberculin skin test-positive, in vitro ESAT-6/CFP10-responsive individuals. Here we have cloned T cells specific for one of these newly identified in vivo expressed Mtb (IVE-TB) antigens, Rv2034. T cells were enriched based on the expression of CD154 (CD40L), which represents a new method for selecting antigen-specific (low frequency) T cells independent of their specific function. An Rv2034-specific CD4+ T-cell clone expressed the Th1 markers T-bet, IFN-γ, TNF-α, IL-2 and the cytotoxicity related markers granzyme B and CD107a as measured by flow cytometry. The clone specifically recognized Rv2034 protein, Rv2034 peptide p81–100 and Mtb lysate. Remarkably, while the recognition of the dominant p81–100 epitope was HLA-DR restricted, the T-cell clone also recognized a neighboring epitope (p88–107) in an HLA-DR- as well as HLA-DQ1-restricted fashion. Importantly, the T-cell clone was able to inhibit Mtb outgrowth from infected monocytes significantly. The characterization of the polyfunctional and Mtb inhibitory T-cell response to IVE-TB Rv2034 at the clonal level provides detailed further insights into the potential of IVE-TB antigens as new vaccine candidate antigens in TB. Our new approach allowed the identification of T-cell subsets that likely play a significant role in controlling Mtb infection, and can be applied to the analysis of T-cell responses in patient populations.

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“…Epitope promiscuity has been shown both experimentally and computationally for peptides derived from different pathogens, including the human papillomavirus [16], HIV [11,15,17,18], and M. tuberculosis [14,32], among others [9,10,12,13]. However, to our knowledge, this is the first study that directly compares promiscuity in multiple pathogens.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown in a variety of pathogens that, even though the adaptive immune response is highly specific, individual HLA class II-restricted peptides [9-13] and HLA class I-restricted peptides [14-18] may bind many different HLA alleles; a trait termed epitope promiscuity. Given the extensive human HLA allele diversity and varied pathogen epitope diversity, we were interested in determining whether the extent of epitope promiscuity varies in pathogens with distinct ecological niches and interactions with human hosts.…”

Section: Introductionmentioning

confidence: 99%

Equivalent T Cell Epitope Promiscuity in Ecologically Diverse Human Pathogens

et al. 2013

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BackgroundThe HLA (human leukocyte antigen) molecules that present pathogen-derived epitopes to T cells are highly diverse. Correspondingly, many pathogens such as HIV evolve epitope variants in order to evade immune recognition. In contrast, another persistent human pathogen, Mycobacterium tuberculosis, has highly conserved epitope sequences. This raises the question whether there is also a difference in the ability of these pathogens’ epitopes to bind diverse HLA alleles, referred to as an epitope’s binding promiscuity. To address this question, we compared the in silico HLA binding promiscuity of T cell epitopes from pathogens with distinct infection strategies and outcomes of human exposure.MethodsWe used computer algorithms to predict the binding affinity of experimentally-verified microbial epitope peptides to diverse HLA-DR, HLA-A and HLA-B alleles. We then analyzed binding promiscuity of epitopes derived from HIV and M. tuberculosis. We also analyzed promiscuity of epitopes from Streptococcus pyogenes, which is known to exhibit epitope diversity, and epitopes of Bacillus anthracis and Clostridium tetani toxins, as these bacteria do not depend on human hosts for their survival or replication, and their toxin antigens are highly immunogenic human vaccines.ResultsWe found that B. anthracis and C. tetani epitopes were the most promiscuous of the group that we analyzed. However, there was no consistent difference or trend in promiscuity in epitopes contained in HIV, M. tuberculosis, and S. pyogenes.ConclusionsOur results show that human pathogens with distinct immune evasion strategies and epitope diversities exhibit equivalent levels of T cell epitope promiscuity. These results indicate that differences in epitope promiscuity do not account for the observed differences in epitope variation and conservation.

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Extensive major histocompatibility complex class I binding promiscuity for Mycobacterium tuberculosis TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)‐B0702 and HLA‐B0801 alleles in TB10.4 CD8⁺ T‐cell responses

Cited by 41 publications

References 42 publications

Insights into HLA-Restricted T Cell Responses in a Novel Mouse Model of Dengue Virus Infection Point toward New Implications for Vaccine Design

Insights into HLA-Restricted T Cell Responses in a Novel Mouse Model of Dengue Virus Infection Point toward New Implications for Vaccine Design

Clonal Analysis of the T-Cell Response to In Vivo Expressed Mycobacterium tuberculosis Protein Rv2034, Using a CD154 Expression Based T-Cell Cloning Method

Equivalent T Cell Epitope Promiscuity in Ecologically Diverse Human Pathogens

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Extensive major histocompatibility complex class I binding promiscuity for Mycobacterium tuberculosis TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)‐B*0702 and HLA‐B*0801 alleles in TB10.4 CD8+ T‐cell responses

Cited by 41 publications

References 42 publications

Insights into HLA-Restricted T Cell Responses in a Novel Mouse Model of Dengue Virus Infection Point toward New Implications for Vaccine Design

Insights into HLA-Restricted T Cell Responses in a Novel Mouse Model of Dengue Virus Infection Point toward New Implications for Vaccine Design

Clonal Analysis of the T-Cell Response to In Vivo Expressed Mycobacterium tuberculosis Protein Rv2034, Using a CD154 Expression Based T-Cell Cloning Method

Equivalent T Cell Epitope Promiscuity in Ecologically Diverse Human Pathogens

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Extensive major histocompatibility complex class I binding promiscuity for Mycobacterium tuberculosis TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)‐B0702 and HLA‐B0801 alleles in TB10.4 CD8⁺ T‐cell responses