Identification of New Alloantigen-Reactive CD8+ Cytotoxic and Suppressor T Cell Subpopulations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3229-3229
Author(s):  
Osnat Bohana-Kashtan ◽  
Hyam Levitsky ◽  
Curt I. Civin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cd4 T Cells ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Suppressor T Cell ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

We sought to develop a better understanding of the T cells involved in the human allogeneic immune response, in order to eventually engineer a donor graft with reduced GVHD-mediating potential, without ablating general immune competence. Prior studies reported that all the activated CD4+ T cells responding to a specific antigen challenge reside within the CD4high population expressing high levels of membrane CD4. We identified a new population of activated CD8+ T cells that developed during an in vitro allogeneic immune response, along with the allo-activated CD4high T cell population. Analogous to activated CD4+ T cells, this new T cell population was distinguished by up-regulated CD8 (and CD38) expression (CD8highCD38+). In accordance with Martins et al. (Blood 2004, 104:3429), we found that the depletion of the CD4highCD38+ population resulted in reduced 2o response to the original 2nd party stimulators. In contrast, depletion of the CD8highCD38+ population resulted in an increased 2o response to 2nd party cells, with no change in the response to 3rd party or CMV antigens. Elevated numbers of CD8highCD38+ T cells potently reduced the 1o and 2o responses to 2nd party, but not to 3rd party cells or CMV antigens. The complementary, non-activated CD8normalCD38− T cell population had no inhibitory effect. Importantly, we found that CD8highCD38+ T cells mediated both a specific cytotoxic response (that could be inhibited by the pan-caspase inhibitor, Z-VAD), and a specific suppressive response toward the original 2nd party stimulators (that was not affected by Z-VAD), and within this CD8highCD38+ population, there was a subpopulation of cytotoxic T cells (perforin+LAMP1+CD56+CD11b+CD11c+) and a subpopulation of non-cytotoxic T cells. Furthermore, we found that although CD8highCD38+ T cells differentially expressed CD28, both CD8highCD38+CD28− and CD8highCD38+CD28− T cells mediated a cytotoxic as well as a suppressor T cell response toward the original 2nd party cells (different from the published suppressive function of CD8+CD28− T cells observed by Liu et al, Int Immunol 1998, 10:775). Upon separation of cytotoxic CD8highCD38+ T cells from suppressor CD8highCD38+ T cells, we will explore the GVHD potential of these 2 novel activated CD8high T cell subpopulations, in a sensitive in vivo xenograft model for GVHD using NOD/SCID/IL2Rγnull immunodeficient mice.

scholarly journals Treatment with bortezomib of human CD4+ T cells preserves natural regulatory T cells and allows the emergence of a distinct suppressor T-cell population

Haematologica ◽  
2009 ◽  
Vol 94 (7) ◽  
pp. 975-983 ◽  
Author(s):  
B. Blanco ◽  
J. A. Perez-Simon ◽  
L. I. Sanchez-Abarca ◽  
T. Caballero-Velazquez ◽  
S. Gutierrez-Cossio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Population ◽  
Cd4 T Cells ◽  
Suppressor T Cell

scholarly journals Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 880 ◽  
Author(s):  
Norwin Kubick ◽  
Patrick C. Henckell Flournoy ◽  
Ana-Maria Enciu ◽  
Gina Manda ◽  
Michel-Edwar Mickael
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Subpopulation ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
Endothelial Integrity

The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer’s drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations’ infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis.

scholarly journals Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy

2020 ◽  
Vol 11 ◽  
Author(s):  
Miren Zuazo ◽  
Hugo Arasanz ◽  
Ana Bocanegra ◽  
Gonzalo Fernandez ◽  
Luisa Chocarro ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Strong Predictor ◽  
Cellular Mechanisms ◽  
Lung Cancer Patients ◽  
Helper Function ◽  
Cell Subpopulations ◽  
Cytotoxic Therapies ◽  
T Cell Subpopulations

PD-L1/PD-1 blockade immunotherapy has significantly improved treatment outcome for several cancer types compared to conventional cytotoxic therapies. However, the specific molecular and cellular mechanisms behind its efficacy are currently unclear. There is increasing evidence in murine models and in patients that unveil the key importance of systemic immunity to achieve clinical responses under several types of immunotherapy. Indeed, PD-L1/PD-1 blockade induces the expansion of systemic CD8+ PD-1+ T cell subpopulations which might be responsible for direct anti-tumor responses. However, the role of CD4+ T cells in PD-L1/PD-1 blockade-induced anti-tumor responses has been less documented. In this review we focus on the experimental data supporting the “often suspected” indispensable helper function of CD4 T cells towards CD8 effector anti-tumor responses in cancer; and particularly, we highlight the recently published studies uncovering the key contribution of systemic CD4 T cells to clinical efficacy in PD-L1/PD-1 blockade therapies. We conclude and propose that the presence of specific CD4 T cell memory subsets in peripheral blood before the initiation of treatments is a strong predictor of responses in non-small cell lung cancer patients. Therefore, development of new approaches to improve CD4 responses before PD-L1/PD-1 blockade therapy could be the solution to increase response rates and survival of patients.

Probing the Impact of AMD3100/GCSF Mobilization on the Peripheral Blood T Cell Content Using a Rhesus Macaque Model: Increased Proportions of FoxP3+/CD4+ T Cells Occur After Mobilization and Leukapheresis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 350-350
Author(s):  
Leslie Kean ◽  
Sharon Sen ◽  
Mark E Metzger ◽  
Aylin Bonifacino ◽  
Karnail Singh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cell Populations ◽  
Macaque Model ◽  
Cd34 Cells ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

Abstract Abstract 350 Introduction: Leukapheresis is a widely utilized modality for collecting hematopoietic stem cells (HSCs). While collection of CD34+ cells with stem-cell activity is the primary goal of most mobilization and leukapheresis procedures, these cells only represent ∼1% of most leukapheresis products. The profile of the non-CD34+ cells is likely influenced by the choice of mobilization strategy, and has the potential to profoundly impact the post-transplant immune milieu of the transplant recipient. Two of the most critical of the CD34-negative cell populations that are collected during leukapheresis include effector and regulatory T cells. Thus, in evaluating mobilization regimens, the impact on these regimens on the mobilization of each of these T cell populations into the peripheral blood should be rigorously evaluated. Methods: We used a rhesus macaque model to determine the impact that mobilization with AMD3100 (a.k.a., Plerixafor or Mozobil®)+ G-CSF (“A+G”) had on peripheral blood CD4+ and CD8+ effector T cell populations as well as on FoxP3+/CD4+ T cells. Three rhesus macaques were mobilized with 10ug/kg SQ of G-CSF for five consecutive days prior to leukapheresis. AMD3100 was administered at 1mg/kg SQ in combination with the last dose of G-CSF two hours prior to leukapheresis. Leukapheresis procedures were performed for two hours using a modified CS3000 Plus cell separator. A peripheral blood sample was taken before cytokine therapy, just prior to leukapheresis following mobilization, one hour during leukapheresis, and at the end of the procedure. These samples were analyzed by multicolor flow cytometry using a BD LSRII flow cytometer. Results: Bulk, effector, and regulatory T cell subpopulations were analyzed flow cytometrically. The proportion of total CD3+ T cells remained stable during mobilization and apheresis: Thus, CD3+ T cells represented 77% of peripheral blood lymphocytes prior to mobilization, and 69% post-apheresis). The balance of CD4+ to CD8+ T cells was also relatively stable. Thus, for one of the three animals tested, the CD4+ and CD8+ proportions remained unchanged after apheresis. For two animals, the average CD4+ % decreased from 67% prior to mobilization to 52% post-apheresis. In these two animals, there was a reciprocal increase in the % of CD3+ T cells that were CD8+ (28% pre-G+A to 40% post-apheresis). The CD28+/CD95- naïve (Tn), CD28+/CD95+ central memory (Tcm) and CD28-/CD95+ effector memory (Tem) subpopulation balance of CD4+ and CD8+ T cells was also determined, by comparing the relative percentages of each subpopulation post-apheresis with their relative percentages prior to mobilization. Compared to their pre-G+A percentages, the post-apheresis CD4+ percentages of Tn, Tcm and Tem were 92%, 93% and 160%, respectively. Thus, the relative proportions of Tn and Tcm CD4+ cells decreased post-apheresis, while the relative proportion of CD4+ Tem increased compared to cytokine administration. For CD8+ T cell subpopulations, the post-apheresis proportions of Tn, Tcm, and Tem compared to their pre-G-CSF proportions were 99%, 70% and 130%, respectively–thus demonstrating the same direction of change as observed for CD4+ T cells. The most striking change in T cell subpopulations occurred in the CD4+/FoxP3+ compartment. The proportion of CD4+ T cells expressing FoxP3 increased by an average of 600% when post-apheresis samples were compared to pre-mobilization samples (FoxP3+ cells were 9.6% of CD4+ T cells post-apheresis versus 1.5% pre-GCSF). An average of 32% of these FoxP3+ CD4+ T cells expressed high levels of CXCR4. CXCR4 expression has been previously documented on human FoxP3+ T cells (Zou et al., Cancer Res, 2004), but this is the first observation of high level expression of CXCR4 on macaque FoxP3+ CD4 T cells, or of their ability to be efficiently mobilized with AMD3100. Discussion: These results suggest that treatment with AMD3100 and G-CSF may mobilize T cell subsets into the peripheral blood that could have beneficial effects during allo-transplantation. The combination of an increase in Tem cells, which have been observed to have decreased ability to cause GvHD (Zheng et al., Blood 2008), along with FoxP3+/CD4+ T cells, which may have regulatory functions, suggests that A+G mobilization could produce an apheresis product with a beneficial CD34-negative cell profile for allogeneic transplantation. Disclosures: No relevant conflicts of interest to declare.

Regulatory T cell/Th17 balance in the pathogenesis of pediatric Behçet disease

Rheumatology ◽  
2021 ◽  
Author(s):  
Anne Filleron ◽  
Tu Anh Tran ◽  
Audrey Hubert ◽  
Alexia Letierce ◽  
Guillaume Churlaud ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Behçet Disease ◽  
Inflammatory Disorder ◽  
Behcet Disease ◽  
Regulatory T Lymphocytes ◽  
Hla Dr ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract Objectives Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in pediatric BD and more precisely to look for a regulatory T lymphocytes (Tregs)/Th17 imbalance. Methods T cell subpopulations were analyzed by flow cytometry in the peripheral blood of pediatric patients with acute (aBD, n = 24), remitting (rBD, n = 12) BD, and in healthy controls (HC, n = 24). Tregs (CD4+CD25hiCD127-/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4, and HLA-DR expression), CD4+ and CD8+ T cells producing interferon-g (Th1 and Tc1) or interleukin (IL)-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and HSP-60) stimulation, were numerated. Results Th17 (1.9 and 5.1 fold) and Tc17 (4.0 and 2.0 fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HC. Th17 frequency under antigenic stimulation was also higher in patients than in HC. The percentage and number of Tregs and activated Tregs in patients and in HC were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+T cells. Conclusion There is a bias toward a Th17 polarization in acute and remitting BD children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+T cell differentiation into Th1 and Th17 cells. Thus, in pediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the helper T cell response.

scholarly journals Elimination of CD4+ suppressor T cells from susceptible BALB/c mice releases CD8+ T lymphocytes to mediate protective immunity against Leishmania.

1989 ◽  
Vol 169 (5) ◽  
pp. 1819-1827 ◽  
Author(s):  
J O Hill ◽  
M Awwad ◽  
R J North
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Leishmania Major ◽  
Delayed Type Hypersensitivity ◽  
Leishmania Infection ◽  
Cd8 T Lymphocytes ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

This study examined the capacity of BALB/c mice that had been depleted of T cell subpopulations to generate a protective immune response to Leishmania major. Thymectomized mice were depleted of either L3T4+ (CD4+) T lymphocytes, Ly2+ (CD8+) T lymphocytes, or both, by treatment with appropriate mAbs. It was found that susceptible mice were rendered resistant to Leishmania by an intravenous infusion of anti-L3T4 mAb. These mice generated an immune response that destroyed the parasite in the primary lesion and in visceral metastatic foci. CD4+ cell-depleted mice also acquired a capacity to mount a sustained delayed-type hypersensitivity (DTH) response to parasite antigens, indicating that DTH, per se, is not a disease-promoting mechanism in the susceptible murine host as has been suggested. Depleting BALB/c mice of CD8+, as well as CD4+ T cells, left them highly susceptible to Leishmania infection, thereby indicating that CD8+ lymphocytes are key protective cells. Our results can be interpreted as showing that the susceptibility of BALB/c mice is due to the generation of CD4+ cells that suppress either the generation or expression of CD8+ T cell-mediated antiLeishmania immunity.

scholarly journals LN Monocytes Limit DC-Poly I:C Induced Cytotoxic T Cell Response via IL-10 and Induction of Suppressor CD4 T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Anita Tewari ◽  
Miglena G. Prabagar ◽  
Sophie L. Gibbings ◽  
Kavita Rawat ◽  
Claudia V. Jakubzick
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Poly I:C ◽  
Cytotoxic T Cell ◽  
Melanoma Model ◽  
Important Addition

Every immune response has accelerators and brakes. Depending on the pathogen or injury, monocytes can play either role, promoting or resolving immunity. Poly I:C, a potent TLR3 ligand, licenses cross-presenting dendritic cells (DC1) to accelerate a robust cytotoxic T cells response against a foreign antigen. Poly I:C thus has promise as an adjuvant in cancer immunotherapy and viral subunit vaccines. Like DC1s, monocytes are also abundant in the LNs. They may act as either immune accelerators or brakes, depending on the inflammatory mediator they encounter. However, little is known about their contribution to adaptive immunity in the context of antigen and Poly I:C. Using monocyte-deficient and chimeric mice, we demonstrate that LN monocytes indirectly dampen a Poly I:C induced antigen-specific cytotoxic T cell response, exerting a “braking” function. This effect is mediated by IL-10 production and induction of suppressor CD4+ T cells. In a metastatic melanoma model, we show that a triple-combination prophylactic treatment consisting of anti-IL-10, tumor peptides and Poly I:C works because removing IL-10 counteracts the monocytic brake, resulting in significantly fewer tumors compared to mice treated with tumor peptides and Poly I:C alone. Finally, in human LN tissue, we observed that monocytes (unlike DCs) express high levels of IL-10, suggesting that anti-IL-10 may be an important addition to treatments. Overall, our data demonstrates that LN monocytes regulate the induction of a robust DC1-mediated immune response. Neutralization of either IL-10 or monocytes can augment Poly I:C-based treatments and enhance T cell cytotoxicity.

scholarly journals Genome Wide DNA Methylation Landscape Reveals Glioblastoma Mediated Epigenetic Modification in Tumor Infiltrating CD4+ T-Cells

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Sreenivasulu Chintala ◽  
Kaleigh Fetcko ◽  
Mario Henriquez ◽  
Sheng Liu ◽  
Jun Wan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Gene Expression Profile ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Epigenetic Modification ◽  
Methylation Status ◽  
T Cell Response

Abstract INTRODUCTION CD4+ helper T (Th) cells initiate and maintain adaptive immune responses and play a critical role in orchestrating effective antitumor immune response. Although recent immunotherapeutic strategies have shown promising results against glioblastoma, the full potential of this modality has yet to be achieved. One of the major limitations of immunotherapy is the poor efficacy of antiglioblastoma T-cell response in the tumor microenvironment. We hypothesized that glioblastoma modulates antitumor T-cell response by epigenetic modification of tumor infiltrating Th cells (TIThC). METHODS To investigate the influence of glioblastoma on TIThCs, we isolated CD4+ T-cells from the tumor and peripheral blood (PB) of 5 steroid naïve patients with newly diagnosed glioblastoma and performed whole-genome bisulfite sequencing (WGBS) as well as RNAseq and identified differentially methylated and expressed genes between the two cell populations. RESULTS Our results show that glioblastoma mediated epigenetic modifications define the molecular characteristics of glioblastoma infiltrating CD4+ T-cells. Tegmentation based WGBS revealed more than 25 000 regions that are methylated differentially in pairwise comparison of TIThC and PB CD4+ T-cells. Methylation status correlated with the gene expression profile with more than 20 000 differentially expressed genes in TIThCs compared to PB. Of the CD4 lineage specific genes, TBX21, GATA3, RORC, and FOXP3, TBX21, GATA3, and FOXP3 showed differential methylation and expression level in TIThC; whereas, RORC only showed difference in methylation status but not in gene expression level. There was a significant difference in overall and CD4 lineage specific methylation and gene expression profile between patients. Pathway analysis of differentially methylated regions and differentially expressed genes indicated several pathways of tumor induced deregulation, including those involved in T-cell activation, lymphocyte differentiation, regulation of immune effector process, and cytokine production. CONCLUSION Glioblastoma multiforme (GBM) regulates antitumor immune response by significant epigenetic reprogramming of TIThC; thus, influencing their lineage specific differentiation and function.

Neopterin estimation compared with the ratio of T-cell subpopulations in persons infected with human immunodeficiency virus-1.

1988 ◽  
Vol 34 (12) ◽  
pp. 2415-2417 ◽  
Author(s):  
D Fuchs ◽  
M Banekovich ◽  
A Hausen ◽  
J Hutterer ◽  
G Reibnegger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immunodeficiency Virus ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

Abstract We measured neopterin, a biochemical indicator for the activation of cell-mediated immune reactions, in urines from 105 individuals at risk of infection with human immunodeficiency virus-1 (HIV-1), 83 of whom were seropositive for antibody to HIV-1. We compared absolute numbers of T-cell subsets (CD4+ helper/inducer T-cells, CD8+ suppressor/cytotoxic T-cells), and the ratio of CD4+ T-cells to CD8+ T-cells with the urinary neopterin concentrations. Concentrations of neopterin in urine were inversely correlated with absolute numbers of CD4+ T-cells and with CD4+/CD8+ ratios in anti-HIV-1 seropositive subjects but not in those seronegative. Various statistical comparisons of the data further demonstrated that neopterin concentrations showed larger differences between anti-HIV-1 seronegative and seropositive subjects than absolute numbers of CD4+ T-cells or CD4+/CD8+ ratios. These results seem to indicate that neopterin concentrations increase earlier in the course of HIV-1 infection, before effects on T-cell subpopulations are detectable, and may further support the suggestion that neopterin measurement could be of use for monitoring infected subjects or predicting the progression of disease.

T-Cell Subpopulations in Head and Neck Carcinoma

1984 ◽  
Vol 92 (4) ◽  
pp. 381-385 ◽  
Author(s):  
Jonas T. Johnson ◽  
Bruce S. Rabin ◽  
Barry Hirsch ◽  
Patricia B. Thearle
Keyword(s):  
T Cells ◽  
T Cell ◽  
Head And Neck ◽  
Cytotoxic T Cells ◽  
Head And Neck Carcinoma ◽  
Prognostic Indicator ◽  
Cell Subpopulation ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Peripheral blood T-cell subpopulations were quantitated with monoclonal antibodies in a group of 27 patients with biopsy-proved squamous cell carcinoma of the head and neck. Abnormal quantitative relationships between helper/inducer T cells (Th) and suppressor/cytotoxic T cells (Ts) were encountered in many patients. Short-term follow-up of these patients did not demonstrate a correlation between these immune parameters and clinical course. Longer follow-up and expansion of the data base will be necessary before a determination can be made of the value of quantitative T-cell subpopulation analysis relative to its use as a prognostic indicator in patients with head and neck cancer.

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