Transcriptional Profile of Tuberculosis Antigen–Specific T Cells Reveals Novel Multifunctional Features

Arlehamn, Cecilia S. Lindestam; Seumois, Grégory; Герасимова, Анна; Huang, Chu‐Yu; Fu, Zheng Qing; Yue, Xiaojing; Sette, Alessandro; Vijayanand, Pandurangan; Peters, Bjoern

doi:10.4049/jimmunol.1401151

Cited by 93 publications

(129 citation statements)

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“…The transcriptional signature of these cells shows that they express molecular features, such as ABCB1 (MDR1), KIT (CD117), CCR2, BAFF, and IL12RB2, thought to be relevant for controlling chronic/latent infections (43). This finding predicts that NTM-based vaccines should elicit CD4 T-cell responses phenotypically similar to those elicited by MTB infection.…”

Section: Discussionmentioning

confidence: 92%

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Arlehamn

Paul

Mele

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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A previous unbiased genome-wide analysis of CD4 Mycobacterium tuberculosis (MTB) recognition using peripheral blood mononuclear cells from individuals with latent MTB infection (LTBI) or nonexposed healthy controls (HCs) revealed that certain MTB sequences were unexpectedly recognized by HCs. In the present study, it was found that, based on their pattern of reactivity, epitopes could be divided into LTBI-specific, mixed reactivity, and HC-specific categories. This pattern corresponded to sequence conservation in nontuberculous mycobacteria (NTMs), suggesting environmental exposure as an underlying cause of differential reactivity. LTBI-specific epitopes were found to be hyperconserved, as previously reported, whereas the opposite was true for NTM conserved epitopes, suggesting that intragenus conservation also influences host pathogen adaptation. The biological relevance of this observation was demonstrated further by several observations. First, the T cells elicited by MTB/NTM cross-reactive epitopes in HCs were found mainly in a CCR6 + CXCR3 + memory subset, similar to findings in LTBI individuals. Thus, both MTB and NTM appear to elicit a phenotypically similar T-cell response. Second, T cells reactive to MTB/NTMconserved epitopes responded to naturally processed epitopes from MTB and NTMs, whereas T cells reactive to MTB-specific epitopes responded only to MTB. Third, cross-reactivity could be translated to antigen recognition. Several MTB candidate vaccine antigens were cross-reactive, but others were MTB-specific. Finally, NTM-specific epitopes that elicit T cells that recognize NTMs but not MTB were identified. These epitopes can be used to characterize T-cell responses to NTMs, eliminating the confounding factor of MTB cross-recognition and providing insights into vaccine design and evaluation.tuberculosis | T-cell epitope | NTM | epitope conservation | T-cell subset

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Section: Discussionmentioning

confidence: 92%

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Arlehamn

Paul

Mele

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…To ensure that asthma-specific molecular features were captured, or at least not lost, across the wide range of circulating T cell subtypes present in vivo, we devised a simple sorting strategy to enrich for human Th2 cells, a subset of CD4 + T cells that is highly relevant to asthma pathogenesis (3, 5). Further, to avoid mistaking differences in the relative abundance of Th2 cells for asthma-specific transcriptional changes, and to capture changes that specifically occur in circulating Th2 cells, we performed transcriptional profiling in pure populations of CCR4-expressing memory CD4 + T cells (CCR4 + CD4 + CD45RA − ; for simplicity, hereafter referred to as Th2 cells), as human Th2 cells are enriched in CD4 + memory T cells that express the chemokine receptor CCR4 + , and are depleted in CCR4 − cells (11, 12, 31). By this approach we also expected to capture asthma-specific changes resulting from T cell activation and differentiation in the host, e.g.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma

Seumois

Zapardiel‐Gonzalo

White

et al. 2016

The Journal of Immunology

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Allergic asthma and rhinitis are two common chronic allergic diseases that affect the lungs and nose, respectively. Both diseases share clinical and pathological features characteristic of excessive allergen-induced type 2 inflammation, orchestrated by memory CD4+ T cells that produce type 2 cytokines (Th2 cells). However, a large majority of subjects with allergic rhinitis do not develop asthma, suggesting divergence in disease mechanisms. Since Th2 cells play a pathogenic role in both these diseases and are also present in healthy non-allergic subjects, we performed global transcriptional profiling to determine whether there are qualitative differences in Th2 cells from subjects with allergic asthma, rhinitis and healthy controls. Th2 cells from asthmatic subjects expressed higher levels of several genes that promote their survival as well as alter their metabolic pathways to favor persistence at sites of allergic inflammation. In addition, genes that enhanced Th2 polarization and Th2 cytokine production were also upregulated in asthma. Several genes that oppose T cell activation were downregulated in asthma, suggesting enhanced activation potential of Th2 cells from asthmatic subjects. Many novel genes with poorly defined functions were also differentially expressed in asthma. Thus, our transcriptomic analysis of circulating Th2 cells has identified several molecules that are likely to confer pathogenic features to Th2 cells that are either unique or common to both asthma and rhinitis.

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“…In addition, T H cell subsets have been classified on the basis of their cytokine profile and functional properties into T H 1, T H 2, T H 17, T H * (T H 1/T H 17), regulatory T cell, and follicular helper (T FH ) T cell subsets (3, 4). Although T lymphocytes with cytotoxic function (CTLs) are predominantly restricted to conventional major histocompatibility complex (MHC) class I–restricted CD8 + T lymphocytes, the existence of MHC class II–restricted T H cells with cytotoxic potential (CD4-CTLs) in humans, nonhuman primates, and mice has been reported for many decades (5, 6).…”

Section: Introductionmentioning

confidence: 99%

Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

et al. 2018

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CD4+ cytotoxic T lymphocytes (CD4-CTLs) have been reported to play a protective role in several viral infections. However, little is known in humans about the biology of CD4-CTL generation, their functional properties, and heterogeneity, especially in relation to other well-described CD4+ memory T cell subsets. We performed single-cell RNA sequencing in more than 9000 cells to unravel CD4-CTL heterogeneity, transcriptional profile, and clonality in humans. Single-cell differential gene expression analysis revealed a spectrum of known transcripts, including several linked to cytotoxic and costimulatory function that are expressed at higher levels in the TEMRA (effector memory T cells expressing CD45RA) subset, which is highly enriched for CD4-CTLs, compared with CD4+ T cells in the central memory (TCM) and effector memory (TEM) subsets. Simultaneous T cell antigen receptor (TCR) analysis in single cells and bulk subsets revealed that CD4-TEMRA cells show marked clonal expansion compared with TCM and TEM cells and that most of CD4-TEMRA were dengue virus (DENV)–specific in donors with previous DENV infection. The profile of CD4-TEMRA was highly heterogeneous across donors, with four distinct clusters identified by the single-cell analysis. We identified distinct clusters of CD4-CTL effector and precursor cells in the TEMRA subset; the precursor cells shared TCR clonotypes with CD4-CTL effectors and were distinguished by high expression of the interleukin-7 receptor. Our identification of a CD4-CTL precursor population may allow further investigation of how CD4-CTLs arise in humans and, thus, could provide insights into the mechanisms that may be used to generate durable and effective CD4-CTL immunity.

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Transcriptional Profile of Tuberculosis Antigen–Specific T Cells Reveals Novel Multifunctional Features

Cited by 93 publications

References 50 publications

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma

Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis

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Transcriptional Profile of Tuberculosis Antigen–Specific T Cells Reveals Novel Multifunctional Features

Cited by 93 publications

References 50 publications

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma

Precursors of human CD4 + cytotoxic T lymphocytes identified by single-cell transcriptome analysis

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Precursors of human CD4 ⁺ cytotoxic T lymphocytes identified by single-cell transcriptome analysis