Unique phenotypes and clonal expansions of human CD4 effector memory T cells re-expressing CD45RA

Tian, Yuan; Babor, Mariana; Lane, Jerome C.; Schulten, Véronique; Patil, Veena S.; Seumois, Grégory; Rosales, Sandy L.; Fu, Zheng Qing; Picarda, Gaëlle; Burel, Julie G.; Zapardiel‐Gonzalo, Jose; Tennekoon, Rashika N.; Silva, Aruna Dharshan De; Premawansa, Sunil; Premawansa, Gayani; Wijewickrama, Ananda; Greenbaum, Jason A.; Vijayanand, Pandurangan; Weiskopf, Daniela; Sette, Alessandro; Peters, Bjoern

doi:10.1038/s41467-017-01728-5

Cited by 223 publications

(231 citation statements)

References 45 publications

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“…TEMRA cells showed a distinct transcriptional profile characterized by high expression of cytotoxic genes (eg. PRF1, CCL4, GZMA, GZMH), consistent with previous observations 25 . Importantly, these cells expressed comparable levels of CD4 and no CD8.…”

Section: (Methods Andsupporting

confidence: 93%

“…These observations highlight the remarkable plasticity of CD4+ T cells and suggest that memory cells retain the ability to respond to cytokines. However, understanding the effects of cytokines on memory T cells is challenging because circulating memory T cells are heterogeneous, comprised of multiple subpopulations such as central and effector memory cells [24][25][26] .…”

mentioning

confidence: 99%

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Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Cano-Gamez

Soskic

Roumeliotis

et al. 2019

Preprint

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AbstractNaïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naïve and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naïve to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.

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Section: (Methods Andsupporting

confidence: 93%

mentioning

confidence: 99%

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Cano-Gamez

Soskic

Roumeliotis

et al. 2019

Preprint

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“…CD4 CTLs have been identified in differentiated T-cell subsets: i.e., effector memory (TEM) and effector memory re-expressing CD45RA (TEMRA) cells, which are often associated with a distinct surface phenotype including CCR7-, CD27-, CD28-, and CD11A+ (31, 32). To understand the CD4+GZMB+ T-cells in the context of differentiation, we constructed single-cell trajectories using the Monocle 2 (version 2.4.0) R package (33); all T cells in TC1 and TC2 were placed on these trajectories based on changes in their transcriptomes (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…The primary function of CD4 T-cells, generally called helper T cells, is the regulation of immune responses using various cytokines, rather than direct elimination of target cells using cytotoxic molecules. Nevertheless, the presence of CD4 T-cells with cytotoxic features, namely CD4 CTLs, has been repeatedly reported in humans and mice (31, 32, 35). The reported fractions of CD4 CTLs are generally as low as a few percent of the total CD4 T-cells in healthy PBMCs (31, 36), whereas the size of the CD4 CTL fraction in the supercentenarians analyzed was on average 25% of T-cells, as measured by RNA-Seq and supported by the independent FACS measurements (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…The association of CD4 CTLs with virus infection suggests that CD4 CTLs have accumulated in supercentenarians at least partially through clonal expansions triggered by repeated viral exposure. Although some important genes such as CRTAM and ADGRG1 ( GPR56 ) have been reported (32, 45), the exact molecular mechanism of the conversion from CD4 helper T-cells to CD4 CTLs is still unclear. Our transcriptome data show the striking similarity of gene expression and differentiation between CD4 CLTs and CD8 CTLs (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians

Hashimoto

Kouno

Ikawa

et al. 2019

Preprint

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Supercentenarians, people who have reached 110 years of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from seven supercentenarians and five younger controls. We identified a marked increase of cytotoxic CD4 T-cells (CD4 CTLs) coupled with a substantial reduction of B-cells as a novel signature of supercentenarians. Furthermore, single-cell T-cell receptor sequencing of two supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15% to 35% of the entire CD4 T-cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.SignificanceExceptionally long-lived people such as supercentenarians tend to spend their entire lives in good health, implying that their immune system remains active to protect against infections and tumors. However, their immunological condition has been largely unexplored. We profiled thousands of circulating immune cells from supercentenarians at single-cell resolution, and identified a large number of CD4 T-cells that have cytotoxic features. This characteristic is very unique to supercentenarians, because generally CD4 T-cells have helper, but not cytotoxic, functions under physiological conditions. We further profiled their T-cell receptors, and revealed that the cytotoxic CD4 T-cells were accumulated through clonal expansion. The conversion of helper CD4 T-cells to a cytotoxic variety might be an adaptation to the late stage of aging.

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Association of immune cell subsets with incident heart failure in two population‐based cohorts

et al. 2022

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Aims Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)]. Methods and results Peripheral blood immune cell subsets were measured in adults from the Multi‐Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 4.4 years with 62% women. In the meta‐analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83–0.99), P = 0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62–0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF. Conclusions We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population‐based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.

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Unique phenotypes and clonal expansions of human CD4 effector memory T cells re-expressing CD45RA

Cited by 223 publications

References 45 publications

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians

Association of immune cell subsets with incident heart failure in two population‐based cohorts

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