HLA-DR phenotypes and blood levels of T cell subsets

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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T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease

Blood ◽

10.1182/blood.v74.2.786.786 ◽

1989 ◽

Vol 74 (2) ◽

pp. 786-792 ◽

Cited By ~ 64

Author(s):

TH Totterman ◽

M Carlsson ◽

B Simonsson ◽

M Bengtsson ◽

K Nilsson

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Healthy Subjects ◽

Lymphocytic Leukemia ◽

Stage Ii ◽

T Cell Subsets ◽

Cd8 Cells ◽

Hla Dr ◽

The Absolute

Abstract Two-color FACS analysis was used to study activated and “functional” T and natural killer (NK) cell subsets of circulating lymphocytes in 23 patients with B-type chronic lymphocytic leukemia (B-CLL) and in 30 healthy subjects. As compared with controls, B-CLL patients had increased absolute numbers of phenotypically activated, HLA-DR+ CD4+ and CD8+ cells and T suppressor/effector (CD11b+CD8+) cells. When patients in Rai stages II through IV (n = 11) were compared with cases in Rai stages O through I (n = 12), the former group of patients had higher numbers of activated CD4+ and CD8+ T cells and decreased levels of suppressor/effector T cells. The absolute numbers of T suppressor/inducer (CD45R+CD4+) cells were elevated in patients with stage O through I disease but within normal range in stage II through IV leukemia. We further showed that the absolute numbers of NK-like (CD16+) cells and their activated counterparts (DR+CD16+) are elevated in B-CLL patients as compared with healthy subjects. The comparison of relative T and NK subsets in the blood of patients and controls showed that the proportions of CD4+, CD8+, and CD16+ cells expressing the activation marker HLA-DR were increased in B-CLL. Furthermore, the percentage of T-suppressor/inducer (CD45R+) cells within the CD4+ population was decreased in the patients. The proportion of T- suppressor/effector (CD11b+) cells within the CD8+ subset was reduced in subjects with stage II-IV disease only. When stimulated in vitro with the T-cell-dependent inducer TPA, B-CLL cells from patients in Rai stages II through IV secreted larger amounts of IgM as compared with cells from stage O through I patients. A positive correlation was observed between the degree of phenotypic activation of CD4+ T-helper cells and their functional capacity to augment IgM secretion by autologous B-CLL cells. Our findings indicate a tumor cell-directed regulatory role of T cells (and possibly NK cells as well) in B-CLL. Furthermore, monitoring of phenotypically activated and functional T- cell subsets may be helpful in the prediction of disease progression and timing of therapy in B-CLL.

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HIV-1-Specific CD11c+ CD8+ T Cells Display Low PD-1 Expression and Strong Anti-HIV-1 Activity

Frontiers in Immunology ◽

10.3389/fimmu.2021.757457 ◽

2021 ◽

Vol 12 ◽

Author(s):

An-Liang Guo ◽

Jin-Fang Zhao ◽

Lin Gao ◽

Hui-Huang Huang ◽

Ji-Yuan Zhang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Subset ◽

T Cell Subsets ◽

Hla Dr ◽

Tnf Α ◽

Treatment Naïve ◽

Vitro Analysis ◽

Hiv 1

Exhaustion of HIV-1-specific CD8+ T cells prevents optimal control of HIV-1 infection. Identifying unconventional CD8+ T cell subsets to effectively control HIV-1 replication is vital. In this study, the role of CD11c+ CD8+ T cells during HIV-1 infection was evaluated. The frequencies of CD11c+ CD8+ T cells significantly increased and were negatively correlated with viral load in HIV-1-infected treatment-naïve patients. HIV-1-specific cells were enriched more in CD11c+ CD8+ T cells than in CD11c- CD8+ T cells, which could be induced by HIV-1-derived overlapping peptides, marking an HIV-1-specific CD8+ T cell population. This subset expressed higher levels of activating markers (CD38 and HLA-DR), cytotoxic markers (granzyme B, perforin, and CD107a), and cytokines (IL-2 and TNF-α), with lower levels of PD-1 compared to the CD11c- CD8+ T cell subset. In vitro analysis verified that CD11c+ CD8+ T cells displayed a stronger HIV-1-specific killing capacity than the CD11c- counterparts. These findings indicate that CD11c+ CD8+ T cells have potent immunotherapeutic efficacy in controlling HIV-1 infection.

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HLA-DR Protein Expression Correlates with Non-Neoplastic T-Cell Infiltration and Predicts Survival in Patients with Primary Mediastinal Large B Cell Lymphoma (PMBCL) Treated with CHOP Chemotherapy.

Blood ◽

10.1182/blood.v114.22.133.133 ◽

2009 ◽

Vol 114 (22) ◽

pp. 133-133 ◽

Cited By ~ 2

Author(s):

Pedro Farinha ◽

Christian Steidl ◽

Lisa M. Rimsza ◽

Kerry J. Savage ◽

Joseph M. Connors ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Research Funding ◽

B Cell Lymphoma ◽

T Cell Subsets ◽

Cell Content ◽

Mhc Ii ◽

Hla Dr ◽

Multi Agent ◽

Large B Cell

Abstract 133 Background: PMBCL represents a unique lymphoma type in the WHO classification and shares overlapping histological and gene expression features with both diffuse large B-cell (DLBCL) and classical Hodgkin lymphoma. Similar to DLBCL, PMBCL may show loss of expression of the major histocompatibility class II (MHC II) antigens, which correlates with inferior patient survival (Rimsza, Blood 2006). MHC II proteins are expressed on antigen-presenting cells and are important in eliciting immune responses. In DLBCL, decreased expression of HLA-DR is related to loss of immunosurveillence. Our aim was to validate HLA-DR as an important prognostic biomarker in PMBCL and correlate it with immune response in a cohort of patients treated with multi-agent chemotherapy. Methods: A tissue microarray block was built with duplicate 0.6mm cores of paraffin embedded diagnostic biopsies from 103 patients treated with CHOP/CHOP-like chemotherapy at the BC Cancer Agency (1980-2005). Standard immunohistochemistry was performed with CD20, HLA-DR (IgG2b), CD3, CD4, CD8, CD57, CD68 and cytotoxic markers (TIA1 & Granzyme B). HLA-DR expression was evaluated using a histoscore (intensity of staining and % of positive malignant cells) and correlated with the content (%) of different non-neoplastic infiltrating T-cell subsets and macrophages. Univariate & multivariate analyses were used to characterize overall survival (OS) and progression free survival (PFS). Results: The median follow-up of living patients was 10 years. The IPI predicted OS (p=0.042) but not PFS. Of the 92 cases with interpretable staining, 32 were positive for HLA-DR and 60 negative, with 10-year OS of 86% vs. 61% (p=0.006) and 2-year PFS of 78% vs. 53% (p=0.018), respectively. A Cox multivariate model established both HLA-DR status and IPI as independent predictors of OS (RR=0.3, 95%CI=0.12–0.75, p=0.01; RR=2.9, 95%CI=1.2–6.9, p=0.06, respectively). HLA-DR expression correlated significantly with increased content of all analyzed T cell markers, especially CD3, CD8 and TIA1 (x2, p<0.001), but not with macrophage content (CD68). Of all non-malignant markers, only TIA1+ cell content significantly correlated with survival. Of the 83 cases with interpretable staining, 43 had more than 10% of infiltrating TIA1+ cells and 40 had less, with 10-year OS of 83% vs. 57% (p=0.0014) and 2-year PFS of 76% vs. 50% (p=0.014), respectively. In multivariate analysis, including IPI and HLA-DR and cytotoxic markers, only TIA1 status was an independent predictor of OS (RR=0.3, 95%CI=0.11–0.63, p=0.003). Conclusions: We validated the negative prognostic importance of loss of HLA-DR expression by neoplastic B cells in PMBCL patients treated with multi-agent chemotherapy in a single institution experience. Loss of HLA-DR expression correlated with decreased numbers of infiltrating benign T cell populations, especially CD8+ and TIA1+ cells, where decreased cytotoxic T cell content correlated independently with inferior survival. This study shows loss of immunogenicity and immunosurveillance are key mechanisms in the response to treatment of PMBCL patients and suggests that specific therapies focused on this pathway may benefit patients. Disclosures: Connors: Roche Canada (F Hoffmann-La Roche): Research Funding. Gascoyne:Roche Canada, Genentech, Lilly, Millennium : Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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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HLA-DR Antigen Expression on Peripheral T Cell Subsets in Pityriasis rosea and Herpes zoster

Dermatology ◽

10.1159/000247769 ◽

1991 ◽

Vol 182 (3) ◽

pp. 160-163 ◽

Cited By ~ 11

Author(s):

T. Yoshiike ◽

Y. Aikawa ◽

H. Wongwaisayawan ◽

H. Ogawa

Keyword(s):

Herpes Zoster ◽

T Cell ◽

Antigen Expression ◽

T Cell Subsets ◽

Pityriasis Rosea ◽

Hla Dr

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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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Time-course analysis of CD25 and HLA-DR expression on lymphocytes in interferon-β1b-treated multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/135245859800400316 ◽

1998 ◽

Vol 4 (3) ◽

pp. 174-177 ◽

Cited By ~ 1

Author(s):

A M Ferrarini ◽

S Sivieri ◽

M Buttarello ◽

A Facchinetti ◽

P Perini ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

T Lymphocytes ◽

Cell Number ◽

Receptor Expression ◽

T Cell Subsets ◽

Hla Dr ◽

T1 And T2 ◽

Pre Treatment ◽

Multiple Sclerosis Patients

To identify immunological markers that could be used to monitor relapsing-remitting multiple sclerosis (RRMS) course/activity during interferon beta 1b (IFNβ1b) therapy, we longitudinally studied HLA-DR and CD25 expression by T lymphocytes in 15 IFNβ1b-treated RRMS patients. Peripheral blood T cell subsets were analysed before therapy (T0), and after 1 (T1), 2 (T2), 3 (T3), 6 (T4) and 12 (T5) months after therapy initiation. HLADR expression and the CD3+HLA-DR+ T cell number showed a peculiar trend in almost all (14/15) the patients: a significant decrease at T1 and T2 followed by a return to pre-treatment levels from T3 to T5. At T1 and T2, eight patients showed an up-regulation of CD25 on CD4, as well as an increase in the CD4+CD25+ cell number. However, a marked, significant reduction of this T cell subset was observed in all the patients at T3, followed by the progressive return to pre-treatment values from T4 to T5. All the patients developed anti-IFNβ1b `binding' antibodies within the first three months of therapy. Our findings demonstrate that: (1) the expression of HLA-DR and CD25 on T cells, as well as the number of circulating CD3+HLA-DR+ and CD4+CD25+ cells, are only transiently reduced in vivo in IFNβ1b-treated RRMS patients, (2) the expression of HLA-DR and CD25 on T lymphocytes cannot be used to monitor MS course/activity during IFNβ1b therapy, (3) the long-lasting beneficial effect of IFNβ1b on RRMS reported in the literature cannot be explained by the down-regulation of MHC class II antigens and/or interleukin-2 receptor expression induced by this cytokine.

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The detailed distribution of T cell subpopulations in immune-stable renal allograft recipients: a single center study

PeerJ ◽

10.7717/peerj.6417 ◽

2019 ◽

Vol 7 ◽

pp. e6417 ◽

Cited By ~ 1

Author(s):

Quan Zhuang ◽

Bo Peng ◽

Wei Wei ◽

Hang Gong ◽

Meng Yu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Renal Allograft ◽

T Cell Subsets ◽

Post Transplantation ◽

Immune State ◽

Hla Dr ◽

Cell Subpopulations ◽

T Cell Subpopulations ◽

Diverse Groups

Background Most renal allograft recipients reach a stable immune state (neither rejection nor infection) after transplantation. However, the detailed distribution of overall T lymphocyte subsets in the peripheral blood of these immune-stable renal transplant recipients remains unclear. We aim to identify differences between this stable immune state and a healthy immune state. Methods In total, 103 recipients underwent renal transplantation from 2012 to 2016 and received regular follow-up in our clinic. A total of 88 of these 103 recipients were enrolled in our study according to the inclusion and exclusion criteria. A total of 47 patients were 1 year post-transplantation, and 41 were 5 years post-transplantation. In addition, 41 healthy volunteers were recruited from our physical examination clinic. Detailed T cell subpopulations from the peripheral blood were assessed via flow cytometry. The parental frequency of each subset was calculated and compared among the diverse groups. Results The demographics and baseline characteristics of every group were analyzed. The frequency of total T cells (CD3+) was decreased in the renal allograft recipients. No difference in the variation of the CD4+, CD8+, and activated (HLA-DR+) T cell subsets was noted among the diverse groups. Regarding T cell receptor (TCR) markers, significant reductions were found in the proportion of γδ T cells and their Vδ2 subset in the renal allograft recipients. The proportions of both CD4+ and CD8+ programmed cell death protein (PD) 1+ T cell subsets were increased in the renal allograft recipients. The CD27+CD28+ T cell proportions in both the CD4+ and CD8+ populations were significantly decreased in the allograft recipients, but the opposite results were found for both CD4+ and CD8+ CD27-CD28- T cells. An increased percentage of CD4+ effector memory T cells and a declined fraction of CD8+ central memory T cells were found in the renal allograft recipients. Conclusion Limited differences in general T cell subsets (CD4+, CD8+, and HLA-DR+) were noted. However, obvious differences between renal allograft recipients and healthy volunteers were identified with TCR, PD1, costimulatory molecules, and memory T cell markers.

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Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Journal of Virology ◽

10.1128/jvi.01424-16 ◽

2016 ◽

Vol 90 (24) ◽

pp. 11259-11278 ◽

Cited By ~ 42

Author(s):

Anmol Chandele ◽

Jaturong Sewatanon ◽

Sivaram Gunisetty ◽

Mohit Singla ◽

Nattawat Onlamoon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dengue Virus ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Cell Receptor ◽

T Cell Subsets ◽

Tcr Signaling ◽

Hla Dr ◽

Ifn Γ

ABSTRACT Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR + CD38 + and HLA-DR − CD38 + effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR + CD38 + subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro . Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.

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