scholarly journals Single‐cell profiling of lineage determining transcription factors in antigen‐specific CD4 + T cells reveals unexpected complexity in recall responses during immune reconstitution

2017 ◽  
Vol 95 (7) ◽  
pp. 640-646 ◽  
Author(s):  
Chansavath Phetsouphanh ◽  
Yin Xu ◽  
Mee Ling Munier ◽  
John J Zaunders ◽  
Anthony D Kelleher
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Single Cell Profiling

scholarly journals Single-cell Profiling of the Response to Poly I:C in Peripheral Blood Mononuclear Cells in Severe Asthma

2020 ◽  
Author(s):  
Ailu Chen ◽  
Maria P Diaz-Soto ◽  
Miguel F Sanmamed ◽  
Taylor Adams ◽  
Jonas Christian Schupp ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Severe Asthma ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Poly I:C ◽  
Peripheral Blood Mononuclear ◽  
Effector Cells ◽  
Single Cell Profiling ◽  
Quantitative Changes

Background: Asthma has been associated with impaired interferon responses. Multiple cell types have been implicated in these impaired responses and may be responsible for increased exacerbations and immunopathology of asthma. Objective: Characterize the single-cell response to Poly I:C of peripheral blood mononuclear cells (PBMCs) of patients with severe asthma (SA). Methods: Two complementary single-cell methods, DropSeq for single-cell RNA sequencing (scRNA-Seq) and mass cytometry (CyTOF), were used to profile PBMCs of SA and healthy controls (HC). Poly I:C and unstimulated cells were analyzed in this study. Results: PBMCs (n=9,414) from five SA (n=6,099) and three HC (n=3,315) were profiled using scRNA-Seq. Six main cell subsets, including CD4+ T cells, CD8+ T cells, natural killer (NK) cells, B cells, dendritic cells (DCs), and monocytes, were identified. CD4+ T cells were the main cell type and demonstrated a pro-inflammatory profile characterized by increased JAK1 expression in unstimulated cells. Following Poly I:C stimulation, PBMCs from SA had a robust induction of interferon pathways compared with HC. Additional analyses to identify core regulators of the enhanced interferon response in SA identified IRF1, STAT1, IRF7, STAT2, and IRF9. CyTOF profiling of Poly I:C and unstimulated PBMCs (n=120,000) from the same individuals (SA=4; HC=2) demonstrated higher numbers of CD8+ effector cells and Th1 CD4+ T cells in unstimulated conditions, followed by a decrease of these two cell subsets after poly I:C stimulation. Conclusion: Single-cell profiling of PBMCs with scRNA-seq and CyTOF in patients with SA identified activation of pro-inflammatory pathways at baseline and strong response to Poly I:C, as well as quantitative changes in CD8+ effector cells and Th1 cells. Thus, transcriptomic and cell quantitative changes are associated with immune cell heterogeneity in severe asthma.

scholarly journals Single-Cell Profiling Defines Transcriptomic Signatures Specific to Tumor-Reactive versus Virus-Responsive CD4+ T Cells

Cell Reports ◽  
2019 ◽  
Vol 29 (10) ◽  
pp. 3019-3032.e6 ◽  
Author(s):  
Assaf Magen ◽  
Jia Nie ◽  
Thomas Ciucci ◽  
Samira Tamoutounour ◽  
Yongmei Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Single Cell Profiling

scholarly journals Designed improvement to T-cell immunotherapy by multidimensional single cell profiling

2021 ◽  
Vol 9 (3) ◽  
pp. e001877
Author(s):  
Irfan N Bandey ◽  
Jay R T Adolacion ◽  
Gabrielle Romain ◽  
Melisa Martinez Paniagua ◽  
Xingyue An ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Adoptive Cell Therapy ◽  
Population Heterogeneity ◽  
Serial Killer ◽  
Car T Cells ◽  
Car T ◽  
Single Cell Profiling ◽  
Killer T Cells

BackgroundAdoptive cell therapy based on the infusion of chimeric antigen receptor (CAR) T cells has shown remarkable efficacy for the treatment of hematologic malignancies. The primary mechanism of action of these infused T cells is the direct killing of tumor cells expressing the cognate antigen. However, understanding why only some T cells are capable of killing, and identifying mechanisms that can improve killing has remained elusive.MethodsTo identify molecular and cellular mechanisms that can improve T-cell killing, we utilized integrated high-throughput single-cell functional profiling by microscopy, followed by robotic retrieval and transcriptional profiling.ResultsWith the aid of mathematical modeling we demonstrate that non-killer CAR T cells comprise a heterogeneous population that arise from failure in each of the discrete steps leading to the killing. Differential transcriptional single-cell profiling of killers and non-killers identified CD137 as an inducible costimulatory molecule upregulated on killer T cells. Our single-cell profiling results directly demonstrate that inducible CD137 is feature of killer (and serial killer) T cells and this marks a different subset compared with the CD107apos (degranulating) subset of CAR T cells. Ligation of the induced CD137 with CD137 ligand (CD137L) leads to younger CD19 CAR T cells with sustained killing and lower exhaustion. We genetically modified CAR T cells to co-express CD137L, in trans, and this lead to a profound improvement in anti-tumor efficacy in leukemia and refractory ovarian cancer models in mice.ConclusionsBroadly, our results illustrate that while non-killer T cells are reflective of population heterogeneity, integrated single-cell profiling can enable identification of mechanisms that can enhance the function/proliferation of killer T cells leading to direct anti-tumor benefit.

Immunology

2017 ◽  
Author(s):  
Dennis J. Hartigan-O’Connor ◽  
Christian Brander
Keyword(s):  
T Cells ◽  
Chronic Inflammation ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Opportunistic Infections ◽  
Cd4 T Cell ◽  
Elite Controllers ◽  
Gastrointestinal Mucosa ◽  
Key Factor ◽  
Hiv Antiretroviral Therapy

The key factor in HIV pathogenesis is the decline in CD4+ T cells with resultant immunodeficiency and chronic inflammation. Depletion of CD4+ T cells from the gastrointestinal mucosa followed by microbial translocation and subsequent immune activation are components of disease progression in untreated patients. Symptomatic and occult opportunistic infections including cytomegalovirus contribute to chronic inflammation in persons infected with HIV. Antiretroviral therapy (ART) results in immune reconstitution, with increases in peripheral CD4+ T cell lymphocytes in most persons infected with HIV, although immune recovery is quite variable. A subset of patients with AIDS will develop immune reconstitution inflammatory syndromes after initiation of ART. Approximately 1% of persons with HIV are able to control infection without the need for ART (“elite” controllers). A variety of immune-based therapies, including hydroxyurea, growth hormone, and statins, are being studied in clinical trials and may ultimately play a role in treating persons with HIV infection.

scholarly journals Single-cell transcriptomics to evaluate HIV latency establishment in primary CD4 T cells

2017 ◽  
Vol 3 ◽  
pp. 11
Author(s):  
L. De Armas ◽  
S. Williams ◽  
K. Russell ◽  
L. Pan ◽  
S. Pahwa
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Hiv Latency

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

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Eddie Cano-Gamez ◽  
Blagoje Soskic ◽  
Theodoros I. Roumeliotis ◽  
Ernest So ◽  
Deborah J. Smyth ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Cd4 T Cells

scholarly journals Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3818-3827 ◽  
Author(s):  
Lis R. V. Antonelli ◽  
Yolanda Mahnke ◽  
Jessica N. Hodge ◽  
Brian O. Porter ◽  
Daniel L. Barber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Interferon Γ ◽  
Effector Memory ◽  
Hiv Patients ◽  
Inflammatory Syndrome

Abstract Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1+, HLA-DR+, and Ki67+ CD4+ T cells than patients without IRIS. Moreover, PD-1+ CD4+ T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.

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