Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease

Nathan, Aparna; Beynor, Jessica I.; Baglaenko, Yuriy; Suliman, Sara; Ishigaki, Kazuyoshi; Asgari, Samira; Huang, Chuan-Chin; Luo, Yang; Zhang, Zibiao; Lopez, Kattya; Arlehamn, Cecilia S. Lindestam; Ernst, Joel D.; Jiménez, Judith; Calderón, Róger; Lecca, Leonid; Rhijn, Ildiko Van; Moody, D. Branch; Murray, Megan; Raychaudhuri, Soumya

doi:10.1038/s41590-021-00933-1

Cited by 79 publications

(70 citation statements)

References 85 publications

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“…Interestingly, these cells share characteristics with a recently described CD4 + CD26 + CD161 + CCR6 + cell subset that expresses IL-17 and IL-22 and was preferentially enriched in a Peruvian cohort of TB non-progressors. 57 These findings warrant further clinical and mechanistic investigation of these cells in clinical studies and animal models.…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2022

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Background Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MR1restricted MAIT cells, CD1b-restricted glucose monomycolate (GMM)-specific T cells, CD1d-restricted NKT cells, and gd T cells, in vaccination against Mycobacterium tuberculosis.Methods We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults.Findings BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of gd T cells as well as a novel subset of CD26 + CD161 + TRAV1-2 À IFN-g-expressing CD4 + T cells in infants.Interpretation Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies.

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Section: Discussionmentioning

confidence: 91%

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

et al. 2022

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“…Several studies suggest an important role for these antigen-specific Th1* cells in the immune response against mycobacteria and they may be a promising candidate for a correlate of protection against Mtb . Th1* cells also share characteristics with a CCR6+ CD4 cell subset recently described as preferentially enriched in a cohort of TB non-progressors compared to those who progressed to active TB [65] . In non-human primates (NHP), antigen-specific CD4 T cells in the PBMCs and bronchoalveolar lavage fluid of rhesus macaques that received BCG intravenously had a similar Th1/Th17 phenotype and importantly the majority of these animals (9/10) were protected from Mtb challenge 6 months post-BCG [4] .…”

Section: Discussionmentioning

confidence: 70%

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

et al. 2021

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Background The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Methods We investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis ( Mtb )-derived peptide pool. Findings Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* (CXCR3+CCR6+) and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. Interpretation The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.

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“…Several studies suggest an important role for these antigen-specific Th1* cells in the immune response against mycobacteria and they may be a promising candidate for a correlate of protection against Mtb . Th1* cells also share characteristics with a CCR6+ CD4 cell subset recently described as preferentially enriched in a cohort of TB non-progressors compared to those who progressed to active TB 44 . In non-human primates (NHP), antigen-specific CD4 T cells in the PBMCs and bronchoalveolar lavage fluid of rhesus macaques that received BCG intravenously had a similar Th1/Th17 phenotype and importantly the majority of these animals (9/10) were protected from Mtb challenge 6 months post-BCG 4 .…”

Section: Discussionmentioning

confidence: 70%

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

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et al. 2021

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The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Here, we investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool. Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.

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Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease

Cited by 79 publications

References 85 publications

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

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

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

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