Effects of BCG vaccination on donor unrestricted T cells in two prospective cohort studies

Gela, Anele; Murphy, Melissa; Rodo, Miguel; Hadley, Kate; Hanekom, Willem A.; Boom, W. Henry; Johnson, John L.; Hoft, Daniel F.; Joosten, Simone A.; Ottenhoff, Tom H. M.; Suliman, Sara; Moody, D. Branch; Lewinsohn, David; Hatherill, Mark; Seshadri, Chetan; Nemes, Elisa; Scriba, Thomas J.; Briel, Libby; Veldtsman, Hellen; Khomba, Nondumiso; Pienaar, Bernadette; Africa, Hadn; Steyn, Marcia

doi:10.1016/j.ebiom.2022.103839

Cited by 19 publications

(18 citation statements)

References 57 publications

(85 reference statements)

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“…Compared to BCG-recipients LTBI-participants had higher frequencies of polyfunctional cDC1 in unstimulated PBMC, while BCG-recipients had higher frequencies of polyfunctional cDC1 and cDC2 after Mtb stimulation (Fig 6D). One of the two recent descriptions of GMM+ Tconv showed their presence in response to BCG administration in infants, but not in adults [55]. On comparing the frequency of CD8+GMM+GranzB+ T cells in BCG-recipients with TB-resisters and LTBI-participants in our study, we also found very small frequencies of this cell subset (≤0.005% out of total lymphocytes) in BCG-recipients, significantly lower compared with either of the Mtb-exposed groups (FDRcorrected p≤0.…”

Section: Immune Responses In Bcg-recipientssupporting

confidence: 56%

“…One of the two recent descriptions of GMM+ Tconv showed their presence in response to BCG administration in infants, but not in adults[55]. On comparing the frequency of CD8+GMM+GranzB+ T cells in BCG-recipients with TB-resisters and LTBI-participants in our study, we also found very small frequencies of this cell subset (≤0.005% out of total lymphocytes) in BCG-recipients, significantly lower compared with either of the Mtb -exposed groups (FDR-corrected p≤0.00013; Fig S7 ).…”

Section: Resultsmentioning

confidence: 99%

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Comparative immune responses toMycobacterium tuberculosisin people with latent infection or sterilizing protection

Jalbert

Liu

Mave

et al. 2022

Preprint

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Tuberculosis (TB) affects 2 billion people worldwide and causes 1.5 million deaths every year. There is great need for new TB vaccines that are more efficacious than the currently licensed BCG vaccine, which provides only limited protection. Our goal was to identify potential targets for new TB vaccines by characterizing the immune responses that distinguish individuals with sterilizing protection against TB (TB-resisters), defined by presence of TB-specific immune responses and absence of latent infection, from individuals with latent TB infection (LTBI-participants). Cryopreserved peripheral blood mononuclear cells (PBMC) from 13 TB-resisters and 10 LTBI-participants were analyzed by high dimensional spectral flow cytometry after overnight M. tuberculosis (Mtb) antigenic stimulation or unstimulated control. Activation of conventional and nonconventional T cells, NK cells, and antigen presenting cells (APC) was compared between the two groups. Compared with LTBI-participants, TB-resisters had significantly higher proportions of conventional and nonconventional T cells expressing granzyme B (GranzB) and PD-1, and of polyfunctional cells in unstimulated and Mtb -stimulated conditions. Conversely LTBI-participants had higher expression of CD25, CD69, CD107a, IL10 and IFNg. An unbiased cluster analysis revealed higher frequency of recently described CD8+GMM+GranzB+ T cells in unstimulated PBMC from TB-resisters than LTBI-participants. APC activation revealed very few differences between TB-resisters and LTBI-participants. An exploratory analysis of responses in 14 BCG-recipients with minimal exposure to TB showed multiple differences with TB-resisters and LTBI-participants in PBMC activation; lower polyfunctionality of T cells and APC in Mtb -stimulated PBMC; and absence of CD8+GMM+GranzB+ T cells. We conclude that combined increased T cell expression of GranzB and checkpoint inhibitors may contribute to immune protection against TB and may be targeted by new vaccines.

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Section: Immune Responses In Bcg-recipientssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Comparative immune responses toMycobacterium tuberculosisin people with latent infection or sterilizing protection

Jalbert

Liu

Mave

et al. 2022

Preprint

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“…Vγ9Vδ2 T cells differentiated into effector cells within the first 10 weeks after birth, and this was likely driven by environmental antigen exposure and was not affected by BCG vaccination ( 55 ). Nevertheless, BCG vaccination at birth does lead to an expansion of total γδ T cells, supporting the possibility that non-Vγ9Vδ2 T cells are preferentially affected in this clinical setting ( 54 ).…”

Section: Discussionmentioning

confidence: 79%

“…High levels of pre-existing immunity prior to BCG revaccination may have impeded our ability to detect clonal expansion. A recently published study directly addresses this limitation by studying infants, who are mycobacteria naïve, yet arrived at a similar conclusion regarding γδ T cell expansion after BCG vaccination ( 54 ). However, even infants are not truly immunologically naive to antigens that modulate DURT cells.…”

Section: Discussionmentioning

confidence: 99%

Durable Expansion of TCR-δ Meta-Clonotypes After BCG Revaccination in Humans

James

Mayer-Blackwell

et al. 2022

Front. Immunol.

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Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for 100 years and prevents disseminated tuberculosis and death in young children. However, it shows only partial efficacy against pulmonary tuberculosis (TB) in adults, so new vaccines are urgently needed. The protective efficacy of BCG depends on T cells, which are typically activated by pathogen-derived protein antigens that bind to highly polymorphic major histocompatibility complex (MHC) molecules. Some T cells recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. Whether live whole cell vaccines, like BCG, can induce durable expansions of DURT cells in humans is not known. We used combinatorial tetramer staining, multi-parameter flow cytometry, and immunosequencing to comprehensively characterize the effect of BCG on activation and expansion of DURT cell subsets. We examined peripheral blood mononuclear cells (PBMC) derived from a Phase I study of South African adults in which samples were archived at baseline, 3 weeks, and 52 weeks post-BCG revaccination. We did not observe a change in the frequency of total mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or γδ T cells at 52 weeks post-BCG. However, immunosequencing revealed a set of TCR-δ clonotypes that were expanded at 52 weeks post-BCG revaccination. These expanded clones expressed the Vδ2 gene segment and could be further defined on the basis of biochemical similarity into several ‘meta-clonotypes’ that likely recognize similar epitopes. Our data reveal that BCG vaccination leads to durable expansion of DURT cell clonotypes despite a limited effect on total circulating frequencies in the blood and have implications for defining the immunogenicity of candidate whole cell TB vaccines.

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“…MAIT cells have been implicated in protective responses to microbial infections and as a result could be an attractive vaccine target because they are not restricted by donor genotype, are relatively abundant in humans, and have capacity for rapid effector function [14,15]. While studies have described MAIT cell responses to systemic vaccination in humans [10,31,32], mice [8] and macaques [33], there are very limited data on how MAIT cells respond to mucosal vaccines. In this longitudinal study, we evaluated MAIT cell response 7 days and one month after S. Typhi strain Ty21a vaccination, and found changes in circulating MAIT cell frequency, activation and homing markers.…”

Section: Discussionmentioning

confidence: 99%

Mucosal-associated invariant T (MAIT) cell responses in Salmonella enterica serovar Typhi strain Ty21a oral vaccine recipients

Trivedi

Cheng

Brintz

et al. 2022

Preprint

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Background. Mucosal–associated invariant T (MAIT) cells are unconventional innate-like T cells abundant in mucosal tissue of humans, and associated with protective responses to microbial infections. MAIT cells have capacity for rapid effector function, including the secretion of cytokines and cytotoxic molecules. However, limited information is available regarding the activity of MAIT cells in mucosal vaccine-mediated immune responses in humans. Methods. We enrolled healthy adults who received a course of oral live-attenuated S. Typhi strain Ty21a vaccine and collected peripheral blood samples pre-vaccination, and at 7 days and one month post-vaccination. We used flow cytometry, cell migration assays, and tetramer decay assay to assess MAIT cell responses. Results. We show that following vaccination, circulating MAIT cells are decreased in frequency but have increased activation markers. Post-vaccine timepoints had higher levels of MAIT cells expressing gut-homing marker integrin α4 β7 and chemokine receptor CCR9, suggesting the potential of MAIT cells to migrate to mucosal sites. While we found higher frequencies of TNFα expression on MAIT cells post-vaccination, we did not find significant differences in expression of other effector molecules, TCR avidity, or cell migration. Conclusions. We show how MAIT cell immune responses are modulated post–vaccination against S. Typhi. This study contributes to our understanding of MAIT cells potential role in oral vaccination against bacterial mucosal pathogens.

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Effects of BCG vaccination on donor unrestricted T cells in two prospective cohort studies

Cited by 19 publications

References 57 publications

Comparative immune responses toMycobacterium tuberculosisin people with latent infection or sterilizing protection

Comparative immune responses toMycobacterium tuberculosisin people with latent infection or sterilizing protection

Durable Expansion of TCR-δ Meta-Clonotypes After BCG Revaccination in Humans

Mucosal-associated invariant T (MAIT) cell responses in Salmonella enterica serovar Typhi strain Ty21a oral vaccine recipients

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