ORCID Profile
0000-0002-4622-1146
Current Organisation
University of Georgia
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Publisher: The American Association of Immunologists
Date: 12-2010
Abstract: Cytokine polyfunctionality has recently emerged as a correlate of effective CTL immunity to viruses and tumors. Although the determinants of polyfunctionality remain unclear, there are published instances of a link between the production of multiple effector molecules and the peptide plus MHC class I molecule avidity of T cell populations. Influenza A virus infection of C57BL/6J mice induces CTL populations specific for multiple viral epitopes, each with varying proportions of monofunctional (IFN-γ+ only) or polyfunctional (IFN-γ+TNF-α+IL-2+) CTLs. In this study, we probe the link between TCR avidity and polyfunctionality for two dominant influenza epitopes (DbNP366 and DbPA224) by sequencing the TCR CDR3β regions of influenza-specific IFN-γ+ versus IFN-γ+IL-2+ cells, or total tetramer+ versus high-avidity CTLs (as defined by the peptide plus MHC class I molecule-TCR dissociation rate). Preferential selection for particular clonotypes was evident for the high-avidity DbPA224-specific set but not for any of the other subsets examined. These data suggest that factors other than TCRβ sequence influence cytokine profiles and demonstrate no link between differential avidity and polyfunctionality.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-01-2014
Abstract: Exactly how memory cells are selected into a recall response to acute viral infection (stochastic or deterministic) remains unresolved. This paper demonstrates definitively that selection of virus-specific CD8 + T cells from memory occurs via active selection of particular T-cell clones after secondary virus infection and that this selection appears to be based on the avidity of the T-cell receptor (TCR) for the virus-derived peptide (p) + major histocompatibility complex class I molecule. We also show that despite clear clonal preferences, there is no global narrowing of epitope-specific TCR ersity in the recall response. We propose that the immune system has evolved such a strategy to optimize cytotoxic T-lymphocyte responses while safeguarding TCR repertoire ersity.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 2017
Publisher: Elsevier BV
Date: 11-2016
Publisher: Springer Science and Business Media LLC
Date: 05-12-2020
DOI: 10.1038/S41577-019-0235-3
Abstract: The immune system is inordinately complex with many interacting components determining overall outcomes. Mathematical and computational modelling provides a useful way in which the various contributions of different immunological components can be probed in an integrated manner. Here, we provide an introductory overview and review of mechanistic simulation models. We start out by briefly defining these types of models and contrasting them to other model types that are relevant to the field of immunology. We follow with a few specific ex les and then review the different ways one can use such models to answer immunological questions. While our ex les focus on immune responses to infection, the overall ideas and descriptions of model uses can be applied to any area of immunology.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-01-2013
Abstract: Ecology is typically thought of as the study of interactions organisms have with each other and their environment and is focused on the distribution and abundance of organisms both within and between environments. On a molecular level, the capacity to probe analogous questions in the field of T-cell immunology is imperative as we acquire substantial datasets both on epitope-specific T-cell populations through high-resolution analyses of T-cell receptor (TCR) use and on global T-cell populations analyzed via high-throughput DNA sequencing. Here, we present the innovative application of existing statistical measures (used typically in the field of ecology), together with unique statistical analyses, to comprehensively assess how the naïve epitope-specific CD8 + cytotoxic T lymphocyte (CTL) repertoire translates to that found following an influenza-virus–specific immune response. Such interrogation of our extensive, cumulated TCR CDR3β sequence datasets, derived from both naïve and immune CD8 + T-cell populations specific for four different influenza-derived epitopes (D b NP 366 , influenza nucleoprotein amino acid residues 366–374 D b PA 224 , influenza acid polymerase amino acid residues 224–233 D b PB1-F2 62 , influenza polymerase B 1 reading frame 2 amino acid residues 62–70 K b NS2 114 , and influenza nonstructural protein 2 amino acid residues 114–121), demonstrates that epitope-specific TCR use in an antiviral immune response is the consequence of a complex interplay between the intrinsic characteristics of the naïve cytotoxic T lymphocyte precursor pool and extrinsic (likely antigen driven) influences, the contribution of which varies in an epitope-specific fashion.
Publisher: Elsevier BV
Date: 11-2016
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 09-2018
Publisher: The American Association of Immunologists
Date: 06-2014
Abstract: Human CMV still remains problematic in immunocompromised patients, particularly after solid organ transplantation. CMV primary disease and reactivation greatly increase the risks associated with incidences of chronic allograft rejection and decreased survival in transplant recipients. But whether this is due to direct viral effects, indirect viral effects including cross-reactive antiviral T cell immunopathology, or a combination of both remains undetermined. In this article, we report the novel TCR signature of cross-reactive HLA-A*02:01 (A2) CMV (NLVPMVATV [NLV])–specific CD8+ T cells recognizing a specific array of HLA-B27 alleles using technical advancements that combine both IFN-γ secretion and multiplex nested RT-PCR for determining paired CDR3α/β sequences from a single cell. This study represents the first evidence, to our knowledge, of the same A2-restricted cross-reactive NLV-specific TCR-α/β signature (TRAV3TRAJ31_TRBV12-4TRBJ1-1) in two genetically distinct in iduals. Longitudinal posttransplant monitoring of a lung transplant recipient (A2, CMV seropositive) who received a HLA-B27 bilateral lung allograft showed a dynamic expansion of the cross-reactive NLV-specific TCR repertoire before CMV reactivation. After resolution of the active viral infection, the frequency of cross-reactive NLV-specific CD8+ T cells reduced to previremia levels, thereby demonstrating immune modulation of the T cell repertoire due to antigenic pressure. The dynamic changes in TCR repertoire, at a time when CMV reactivation was subclinical, illustrates that prospective monitoring in susceptible patients can reveal nuances in immune profiles that may be clinically relevant.
Publisher: Springer Science and Business Media LLC
Date: 05-2017
DOI: 10.1038/NATURE22329
Publisher: Springer Science and Business Media LLC
Date: 28-06-2019
DOI: 10.1038/S41467-019-10661-8
Abstract: The magnitude of T cell responses to infection is a function of the naïve T cell repertoire combined with the context and duration of antigen presentation. Using mass spectrometry, we identify and quantify 21 class 1 MHC-restricted influenza A virus (IAV)-peptides following either direct or cross-presentation. All these peptides, including seven novel epitopes, elicit T cell responses in infected C57BL/6 mice. Directly presented IAV epitopes maintain their relative abundance across distinct cell types and reveal a broad range of epitope abundances. In contrast, cross-presented epitopes are more uniform in abundance. We observe a clear disparity in the abundance of the two key immunodominant IAV antigens, wherein direct infection drives optimal nucleoprotein (NP) 366–374 presentation, while cross-presentation is optimal for acid polymerase (PA) 224–233 presentation. The study demonstrates how assessment of epitope abundance in both modes of antigen presentation is necessary to fully understand the immunogenicity and response magnitude to T cell epitopes.
Publisher: Cold Spring Harbor Laboratory
Date: 17-03-2020
DOI: 10.1101/2020.03.13.20034892
Abstract: As COVID-19 continues to spread, public health interventions are crucial to minimize its impact. The most desirable goal is to drive the pathogen quickly to extinction. This generally involves applying interventions as strongly as possible, which worked for SARS, but so far has failed for COVID-19. If fast eradication is not achievable, the next best goal is to delay the spread and minimize cases and burden on the health care system until suitable drugs or vaccines are available. This suppression approach also calls for strong interventions, potentially applied for a long time.
Publisher: Proceedings of the National Academy of Sciences
Date: 19-01-2016
Abstract: Compromised CD8 + T-cell immunity is associated with significant morbidity and mortality in the elderly. Whereas the number of naïve CD8 + T cells declines with age, the drivers of loss and consequences for clonal composition are unclear. We show that aging disproportionately impacts small naïve CD8 + T-cell populations. For one CD8 + T-cell population, loss of ersity was minimally attributable to expansion but rather was associated with diminished cell number and selective retention of cells exhibiting markers of heightened self, but not foreign, recognition. Thus, vaccine formulations for the elderly may benefit from targeting naïve antigen-specific populations with relatively high precursor frequency and self-reactivity, and retention of high-quality T cells may be achieved through repeated low-level T-cell receptor stimulation.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 12-2019
Abstract: BACKGROUND: It is very difficult to observe tuberculosis (TB) transmission chains and thus, identify superspreaders. We investigate cough duration as a proxy measure of transmission to assess the presence of potential TB superspreaders. DESIGN: We analyzed six studies from China, Peru, The Gambia and Uganda, and determined the distribution of cough duration and compared it with several theoretical distributions. To determine factors associated with cough duration, we used linear regression and boosted regression trees to examine the predictive power of patient, clinical and environmental characteristics. RESULTS: We found within-study heterogeneity in cough duration and strong similarities across studies. Approximately 20% of patients contributed 50% of total cough days, and around 50% of patients contributed 80% of total cough days. The cough duration distribution suggested an initially increasing, and subsequently, decreasing hazard of diagnosis. While some of the exposure variables showed statistically significant associations with cough duration, none of them had a strong effect. Multivariate analyses of different model types did not produce a model that had good predictive power. CONCLUSION: We found consistent evidence for the presence of supercoughers, but no characteristics predictive of such in iduals.
Publisher: Public Library of Science (PLoS)
Date: 23-05-2019
Publisher: Public Library of Science (PLoS)
Date: 18-06-2015
No related grants have been discovered for Andreas Handel.