Differential polarization and activation dynamics of systemic T helper cell subsets after aneurysmal subarachnoid hemorrhage (SAH) and during post-SAH complications

AbstractAneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications, such as cerebral vasospasm (CVS), delayed cerebral ischemia or seizures to mention a few, are mainly responsible for the poor clinical outcome. Inflammation plays an indispensable role during early brain injury (EBI) and delayed brain injury (DBI) phases over which these complications arise. T helper cells are the major cytokine secreting cells of adaptive immunity that can polarize to multiple functionally unique sub-populations. Here, we investigate different CD4+ T cell subsets during EBI and DBI phases after SAH, and their dynamics during post-SAH complications. Peripheral venous blood from 15 SAH patients during EBI and DBI phases, was analyzed by multicolour flowcytometry. Different subsets of CD3+ CD4+ T cells were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs were defined by CD25hiCD127lo. The analysis of activation states was done by the expression of stable activation markers CD38 and HLA-DR. Interestingly, compared to healthy controls, Tregs were significantly increased during both EBI and DBI phases. Different activation states of Tregs showed differential significant increase during EBI and DBI phases compared to controls. HLA-DR− CD38+ Tregs were significantly increased during DBI phase compared to EBI phase in SAH patients developing CVS, seizures and infections. However, HLA-DR− CD38− Tregs were significantly reduced during EBI phase in patients with cerebral ischemia (CI) compared to those without CI. HLA-DR− CD38− Th2 cells were significantly increased during EBI phase compared to controls. A significant reduction in Th17/Tregs and HLA-DR− CD38+ Th17/Tregs ratios was observed during both EBI and DBI phases compared to controls. While HLA-DR− CD38− Th17/Tregs and HLA-DR− CD38− Th1/Th2 ratios were impaired only during EBI phase compared to controls. In conclusion, CD4+ T cell subsets display dynamic and unique activation patterns after SAH and during the course of the manifestation of post-SAH complications, which may be helpful for the development of precision neurovascular care. However, to claim this, confirmatory studies with larger patient cohorts, ideally from different ethnic backgrounds, are required. Moreover, our descriptive study may be the grounds for subsequent lab endeavors to explore the underlying mechanisms of our observations.

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Abstract TP460: Regulatory T-Cells and CD4+ T Helper Cell Subsets Are Differentially Regulated and Express Distinct Activation States After Aneurysmal Subarachnoid Hemorrhage (SAH) and During Post-SAH Complications

Stroke ◽

10.1161/str.51.suppl_1.tp460 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Shafqat R Chaudhry ◽

Sajjad Muhammad

Keyword(s):

T Cells ◽

Subarachnoid Hemorrhage ◽

T Cell ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Treg Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Th2 Cells ◽

T Helper ◽

Hla Dr

Background: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications after aneurysm treatment lead to poor clinical outcome. Current research suggests critical role of inflammation during early and delayed brain injury phases over which these complications arise. T helper cells can polarize to multiple functionally unique subsets. Here, we investigate different CD4+ T cell subsets during these brain injury phases after SAH and their dynamics during post-SAH complications. Methods: Anticoagulated peripheral venous blood was obtained from 15 SAH patients on days 1 and 7, and once from healthy controls. After erythrocyte lysis and single cell wash, 1 million cells were stained with different anti-human mouse monoclonal antibodies and were acquired on BD LSR Fortessa. Lymphocytes were gated based on low side scatter and high CD45 expression. Different CD3+CD4+ T cell subsets were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs by CD25 hi and CD127 lo . SAH patients were dichotomized based on presence or absence of different post-SAH complications (hydrocephalus, seizures, CVS, cerebral ischemia) to assess association of T cell subsets with these complications. Results: Total CD4+ T cells were significantly increased after SAH. Interestingly, Th2 cells were significantly decreased and Th17 cells increased on day 7 compared to day 1 after SAH. However, regulatory T-cells were significantly increased on both assessment days compared to controls. The analysis of activation states was done by CD38 and HLA-DR expression. Th1 and Treg cells were significantly increased on day 1 in SAH patients who developed seizures and CVS, respectively. HLA-DR + CD38 + Th2 cells significantly increased on day 1 in SAH patients who developed hydrocephalus, whereas HLA-DR - CD38 - Th1 cells significantly increased on day 1 in patients with infections. HLA-DR - CD38 - Treg cells were significantly reduced on day 1 and day 7 in patients developing cerebral ischemia . Conclusion: CD4+ T cell subsets and Treg cells display dynamic patterns after SAH, and show a distinct pattern of polarization and activation states in specific post-SAH complications.

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Responsiveness of HIV-specific CD4 T cells to PD-1 blockade

Blood ◽

10.1182/blood-2010-12-328070 ◽

2011 ◽

Vol 118 (4) ◽

pp. 965-974 ◽

Cited By ~ 109

Author(s):

Filippos Porichis ◽

Douglas S. Kwon ◽

Jennifer Zupkosky ◽

Daniel P. Tighe ◽

Ashley McMullen ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cytokine Secretion ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Disease Stage ◽

T Helper ◽

The Impact

Abstract Defining the T helper functions impaired by programmed death–1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-γ), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD-1high sorted CD4 T-cell subsets. Compared with PD-1high HIV-specific CD8 T cells, PD-1high HIV-specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets.

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Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells

Blood ◽

10.1182/blood-2010-11-317321 ◽

2011 ◽

Vol 117 (24) ◽

pp. 6532-6541 ◽

Cited By ~ 147

Author(s):

Bastian Hoechst ◽

Jaba Gamrekelashvili ◽

Michael P. Manns ◽

Tim F. Greten ◽

Firouzeh Korangy

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cd4 T Cells ◽

Th17 Cells ◽

Human Peripheral Blood ◽

Myeloid Cells ◽

T Cell Subsets ◽

T Helper ◽

Hla Dr

Abstract CD4+ T helper cell differentiation is essential for mounting robust immune responses without compromising unresponsiveness toward self-tissue. Here, we show that different subsets of myeloid cells isolated from human peripheral blood modulate TGF-β–dependent CD4+ T-cell developmental programs ex vivo. Human CD14+HLA-DR−/low myeloid-derived suppressor cells (MDSCs) induce Foxp3+ regulatory T cells, whereas CD14+HLA-DR+ monocytes promote generation of IL-17–secreting RORc+ Th17 cells when cocultured with naive CD4+ T cells. More importantly, not only do these 2 subsets modulate the de novo induction of Tregs and Th17 cells from CD4+ T cells, but MDSCs also catalyze the transdifferentiation of Foxp3+ regulatory T cells from monocyte-induced Th17 cells. The mechanism of such Th17 plasticity is dependent on MDSC-derived TGF-β and retinoic acid. Our results identify a previously unknown feature of the different subsets of CD14+ myeloid cells namely their pivotal role in immune response regulation and plasticity of CD4+ T helper cells. We propose that different subsets of myeloid cells in humans can orchestrate the differentiation of naive CD4+ T cells into effector/regulatory T-cell subsets. The balance between these 2 subsets can impact the outcome of immune reaction from inflammation to tolerance.

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Emerging Markers of Early Brain Injury and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

World Neurosurgery ◽

10.1016/j.wneu.2017.07.114 ◽

2017 ◽

Vol 107 ◽

pp. 148-159 ◽

Cited By ~ 26

Author(s):

Fawaz Al-Mufti ◽

Krishna Amuluru ◽

Brendan Smith ◽

Nitesh Damodara ◽

Mohammad El-Ghanem ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury

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Measuring the Impact of Delayed Cerebral Ischemia on Neuropsychological Outcome After Aneurysmal Subarachnoid Hemorrhage—Protocol of a Swiss Nationwide Observational Study (MoCA–DCI Study)

Neurosurgery ◽

10.1093/neuros/nyy155 ◽

2018 ◽

Vol 84 (5) ◽

pp. 1124-1132 ◽

Cited By ~ 5

Author(s):

Martin N Stienen ◽

Christian Fung ◽

Philippe Bijlenga ◽

Daniel W Zumofen ◽

Rodolfo Maduri ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Cerebral Ischemia ◽

Observational Study ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Patient Specific ◽

Neuropsychological Outcome ◽

The Relationship ◽

Baseline Examination

AbstractBACKGROUNDThe exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results.OBJECTIVETo evaluate the relationship between DCI and neuropsychological outcome after aSAH by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 mo with a baseline examination before the DCI-period (part 1). To determine the reliability of the MoCA, when applied in an ICU setting (part 2).METHODSProspective, multicenter, and observational study performed at all Swiss neurovascular centers. For part 1, n = 240 consecutive aSAH patients and for part 2, n = 50 patients with acute brain injury are recruited.EXPECTED OUTCOMESPart 1: Effect size of the relationship between DCI and neuropsychological outcome (MoCA). Part 2: Reliability measures for the MoCA.DISCUSSIONThe institutional review boards approved this study on July 4, 2017 under case number BASEC 2017-00103. After completion, the results will be offered to an international scientific journal for peer-reviewed publication. This study determines the exact impact of DCI on the neuropsychological outcome after aSAH, unbiased by confounding factors such as early brain injury or patient-specific characteristics. The study provides unique insights in the neuropsychological state of patients in the early period after aSAH.

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CVID patients with autoimmunity have elevated T cell expression of granzyme B and HLA-DR and reduced levels of Treg cells

Journal of Clinical Pathology ◽

10.1136/jclinpath-2012-201046 ◽

2012 ◽

Vol 66 (2) ◽

pp. 146-150 ◽

Cited By ~ 25

Author(s):

Clive R D Carter ◽

Ganesha Aravind ◽

Natuley L Smalle ◽

June Y Cole ◽

Sinisa Savic ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Granzyme B ◽

Treg Cells ◽

T Cell Subsets ◽

Activated T Cells ◽

Activation Markers ◽

Hla Dr

AimsCommon variable immunodeficiency (CVID) is a primary antibody immunodeficiency with approximately 20% of patients reporting additional autoimmune symptoms. The primary aim of this study was to compare the levels of activated and regulatory T cells (Treg cells) in CVID patients in an attempt to clarify their possible interactions leading to the generation of autoimmunity.MethodsImmunophenotyping of T cells was performed by flow cytometry using a whole blood approach. Surface expression of human leukocyte antigen HLA class II DR and intracellular levels of granzyme B in T cell subsets were assessed; Treg levels were measured using CD4 CD25, FOXp3 and CTLA-4.ResultsCVID patients had higher levels of granzyme B and HLA-DR on CD8+ T cells compared with control values (mean of 59% vs 30% and 45% vs 21%, respectively). Patients also had reduced levels of Treg cells compared with control values (con mean=3.24% vs pat=2.54%). Patients with autoimmunity (5/23) had a similar level of T cell activation markers to the rest of the patients but with lower Treg cells (mean of 1.1%) and reduced CD25 and CTLA-4 expression. Patients with autoimmunity had a higher ratio of activated to Treg cells compared with patients with no autoimmune symptoms.ConclusionsThese results highlight that reduced levels of Treg cells were associated with elevated levels of activated T cells, suggesting that reduced Treg cells in these patients may have functional consequences in allowing exaggerated T cell responses.

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