Limited recognition of Mycobacterium tuberculosis-infected macrophages by polyclonal CD4 and CD8 T cells from the lungs of infected mice

Patankar, Yash R.; Sutiwisesak, Rujapak; Boyce, Shayla; Lai, Rocky; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro; Behar, Samuel M.

doi:10.1038/s41385-019-0217-6

Cited by 48 publications

(51 citation statements)

References 52 publications

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“…Thus, these two bacterial strains elicit CD4 T cell responses that had a similar capacity to recognize infected macrophages. There was little or no recognition of infected macrophages by CD8 T cells at a low MOI, as previously reported [ 30 ]. Contrary to our prediction, Erdman-elicited CD8 T cells, but not 667-elicited CD8 T cells, recognized H37Rv-infected macrophages at a high MOI ( Fig 5B ).…”

Section: Resultssupporting

confidence: 83%

“…To further test this hypothesis, we determined whether abrogation of the immunodominant TB10.4 4−11 epitope resulted in an expansion of CD8 T cells that better recognized Mtb-infected macrophages. Therefore, we quantified T cell recognition of Mtb-infected macrophages by the Mtb-infected macrophage intracellular cytokine staining assay (MIM-ICS) [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

“…Pulmonary T cells were purified from the Erdman- or 667-infected C57BL/6J mice and co-cultured with H37Rv-infected macrophages. IFNγ production was measured by the MIM-ICS assay as a readout of T cell recognition [ 30 ]. CD4 T cells from Erdman- or 667-infected C57BL/6J mice recognized H37Rv-infected macrophages similarly, and in a dose-dependent manner ( Fig 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…To test this hypothesis, we engineered isogenic strain Erdman strains with the EsxH A10T polymorphism, to determine how the overall CD8 T cell response would change in the absence of the TB10.4 4−11 immunodominant epitope. The ability of polyclonal CD8 T cells, elicited in the presence or absence of the TB10.4 4−11 epitope, to recognize Mtb-infected macrophages was measured by the MIM-ICS assay [ 30 ]. Two different aspects of CD8 responses were assessed by this assay: 1) the specificity and frequency of T cells elicited by Mtb in vivo (i.e., T cell priming); and 2) processing and presentation of Mtb antigens by infected macrophages in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…10 μM peptides and uninfected TGPMs were used as controls. Purified T cells from Mtb-infected mice were added and a standard ICS protocol was used [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

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A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response

et al. 2020

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CD8 T cells provide limited protection against Mycobacterium tuberculosis (Mtb) infection in the mouse model. As Mtb causes chronic infection in mice and humans, we hypothesize that Mtb impairs T cell responses as an immune evasion strategy. TB10.4 is an immunodominant antigen in people, nonhuman primates, and mice, which is encoded by the esxH gene. In C57BL/6 mice, 30–50% of pulmonary CD8 T cells recognize the TB10.4 4−11 epitope. However, TB10.4-specific CD8 T cells fail to recognize Mtb-infected macrophages. We speculate that Mtb elicits immunodominant CD8 T cell responses to antigens that are inefficiently presented by infected cells, thereby focusing CD8 T cells on nonprotective antigens. Here, we leverage naturally occurring polymorphisms in esxH , which frequently occur in lineage 1 strains, to test this “decoy hypothesis”. Using the clinical isolate 667, which contains an EsxH A10T polymorphism, we observe a drastic change in the hierarchy of CD8 T cells. Using isogenic Erd.EsxH A10T and Erd.EsxH WT strains, we prove that this polymorphism alters the hierarchy of immunodominant CD8 T cell responses. Our data are best explained by immunodomination, a mechanism by which competition for APC leads to dominant responses suppressing subdominant responses. These results were surprising as the variant epitope can bind to H2-K b and is recognized by TB10.4-specific CD8 T cells. The dramatic change in TB10.4-specific CD8 responses resulted from increased proteolytic degradation of A10T variant, which destroyed the TB10.4 4-11 epitope. Importantly, this polymorphism affected T cell priming and recognition of infected cells. These data support a model in which nonprotective CD8 T cells become immunodominant and suppress subdominant responses. Thus, polymorphisms between clinical Mtb strains, and BCG or H37Rv sequence-based vaccines could lead to a mismatch between T cells that are primed by vaccines and the epitopes presented by infected cells. Reprograming host immune responses should be considered in the future design of vaccines.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…10 μM peptides and uninfected TGPMs were used as controls. Purified T cells from Mtb-infected mice were added and a standard ICS protocol was used [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

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A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response

et al. 2020

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Self‐Delivering Nanodrugs Developed via Small‐Molecule‐Directed Assembly and Macrophage Cloaking for Sonodynamic‐Augmented Immunotherapy

Xie

Liu

Wang

et al. 2022

Adv Healthcare Materials

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The self‐delivery of sonosensitizers and immunomodulators to tumor areas, which is highly recommended for enhancing sonodynamic immunotherapy, remains a challenge. Herein, a self‐delivering nanodrug (HB‐NLG8189, drug loading: ≈100 wt%) is developed by the small‐molecule self‐assembly of "HB" (a new clinical photosensitizer) and NLG8189 (indoleamine‐(2,3)‐dioxygenase (IDO) pathway inhibitor) for sonodynamic‐augmented immunotherapy; this preparation method ensures the absence of excipient‐related toxicity and immunogenicity. To evade immune recognition and prolong the circulation time, the HB‐NLG8189 nanodrugs are camouflaged using macrophage cell membranes (MPCMs). The constructed HB‐NLG8189@MPCM nanodrugs show an ability to preferentially accumulate within tumors. Upon ultrasound triggering, the HB‐NLG8189@MPCM is able to generate reactive oxygen species efficiently for robust sonodynamic therapy; it induces immunogenic cell death, initiates an antitumor immune response to activate tumor‐specific effector T cells, and promotes the secretion of inflammatory cytokines. The concomitant delivery of NLG8189 reverses the immunosuppressive tumor microenvironment by restraining IDO‐1 activation and the intratumoral infiltration of regulatory T cells. Sonodynamic‐augmented immunotherapy with HB‐NLG8189@MPCM significantly inhibits the growth of both primary and distant tumors with little systemic toxicity. The biomimetic self‐delivery nanodrug provides a promising paradigm for improving sonodynamic immunotherapy.

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The MegaPool Approach to Characterize Adaptive CD4+ and CD8+ T Cell Responses

da Silva Antunes,

Weiskopf,

Sidney

et al. 2023

Current Protocols

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Epitopes recognized by T cells are a collection of short peptide fragments derived from specific antigens or proteins. Immunological research to study T cell responses is hindered by the extreme degree of heterogeneity of epitope targets, which are usually derived from multiple antigens; within a given antigen, hundreds of different T cell epitopes can be recognized, differing from one individual to the next because T cell epitope recognition is restricted by the epitopes’ ability to bind to MHC molecules, which are extremely polymorphic in different individuals. Testing large pools encompassing hundreds of peptides is technically challenging because of logistical considerations regarding solvent‐induced toxicity. To address this issue, we developed the MegaPool (MP) approach based on sequential lyophilization of large numbers of peptides that can be used in a variety of assays to measure T cell responses, including ELISPOT, intracellular cytokine staining, and activation‐induced marker assays, and that has been validated in the study of infectious diseases, allergies, and autoimmunity. Here, we describe the procedures for generating and testing MPs, starting with peptide synthesis and lyophilization, as well as a step‐by‐step guide and recommendations for their handling and experimental usage. Overall, the MP approach is a powerful strategy for studying T cell responses and understanding the immune system's role in health and disease. © 2023 Wiley Periodicals LLC.Basic Protocol 1: Generation of peptide pools (“MegaPools”)Basic Protocol 2: MegaPool testing and quantitation of antigen‐specific T cell responses

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Limited recognition of Mycobacterium tuberculosis-infected macrophages by polyclonal CD4 and CD8 T cells from the lungs of infected mice

Cited by 48 publications

References 52 publications

A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response

A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response

Self‐Delivering Nanodrugs Developed via Small‐Molecule‐Directed Assembly and Macrophage Cloaking for Sonodynamic‐Augmented Immunotherapy

The MegaPool Approach to Characterize Adaptive CD4+ and CD8+ T Cell Responses

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