Effect of 2,3,7,8-Tetrachloro-di-benzo-p-dioxin on T Cell Subpopulations in the Thymus and Spleen of Mice with Chronic Toxoplasma gondii Infection

2000 ◽  
Vol 19 (5) ◽  
pp. 323-329 ◽  
Author(s):  
Marquea D. King ◽  
David S. Lindsay ◽  
Marion F. Ehrich ◽  
Mitzi Nagarkatti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cd8 T Cells ◽  
Brain Lesion ◽  
Environmental Pollutant ◽  
T Cell Subsets ◽  
Double Positive ◽  
Significant Difference ◽  
Tcdd Treatment

In the current study, the effect of exposure to the environmental pollutant, 2,3,7,8-tetrachloro-di-benzo- p-dioxin (TCDD), on mice having chronic infection with Toxoplasma gondii was investigated. For this purpose, four groups of mice were used—mice treated with vehicle, mice treated with TCDD alone, mice infected with T. gondii alone, and mice receiving a combination of TCDD treatment and T. gondii infection. Histological examination and tissue cyst enumeration were performed to indicate the level of infection of the brain. The immune status was studied by enumerating the cellularity as well as the percentages and absolute numbers of the lymphocyte subsets based on the expression of CD4 and CD8 markers in the thymus and spleen. Our studies demonstrated that there was a significant decrease in the total number of thymocytes in TCDD-treated mice that were either uninfected or infected with T. gondii when compared to vehicle controls. However, there was no significant difference observed in thymic cellularity in mice that were infected with T. gondii alone when compared to the uninfected vehicle controls. In addition, the ratio and the total numbers of CD4+, CD8+, CD4–CD8–(double negative, DN) and CD4+CD8+ (double positive, DP) T cell subsets in the thymus from various groups were determined. There was no change in the percentages of T cell subsets in TCDD-treated mice or T. gondii-infected mice when compared to the vehicle controls. However, there was a decrease in the percentage of DPT cells and an increase in the DN and CD8+ T cells in mice that received a combination of TCDD-treatment and T. gondii infection when compared to mice receiving the vehicle or TCDD-treatment alone or infection with T. gondii alone. There was also a decrease in the absolute numbers of the DP and CD4+ T cells and an increase in the CD8+ T cells in the thymus of mice receiving the combination of TCDD-treatment and T. gondii infection when compared to vehicle controls. The splenic cellularity as well as the percentage and absolute numbers of the CD4+ and CD8+ T cell subsets and the non-T cells were not altered in all the groups tested. The natural history of T. gondii infection was not altered following TCDD treatment as demonstrated by no significant differences in brain lesion scores and the number of tissue cysts in the brains of these mice.

549 Characterizing double positive T cells in the tumor microenvironment: a tale of promiscuous cell fates

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A586-A586
Author(s):  
Sara Schad ◽  
Andrew Chow ◽  
Heng Pan ◽  
Levi Mangarin ◽  
Roberta Zappasodi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Human Melanoma ◽  
B16 Melanoma ◽  
T Cell Subsets ◽  
Double Positive ◽  
Cell Fates ◽  
Single Positive

BackgroundCD4 and CD8 T cells are genetically and functionally distinct cell subsets of the adaptive immune system that play pivotal roles in immune surveillance and disease control. During development in the thymus, transcription factors ThPOK and Runx3 regulate the differentiation and maturation of these two lineages into single positive T cells that enter the periphery with mutually exclusive expression of either the CD4 or CD8 co-receptor.1–2 Despite our expectation that these two cell fates are fixed, mature CD4+CD8+ double positive (DP) T cells have been described in the context of numerous immunological responses, including cancer, but their molecular and functional properties and therapeutic relevance remain controversial and largely unknown.3–5MethodsOur lab has identified and characterized a heterogenous DP T cell population in murine and human melanoma tumors comprised of CD4 and CD8 T cells re-expressing the opposite co-receptor and a parallel uptake in the opposite cell type’s phenotype and function. Using CD4 (Trp1) and CD8 (Pmel) transgenic TCR T cells specific to B16 melanoma antigens gp75 and gp100 respectively, we demonstrate the re-expression of the opposite co-receptor following adoptive T cell transfer in B16 melanoma tumor bearing mice.ResultsSpecifically, up to 50% of transferred CD4 Trp1 T cells will re-express CD8 to become a DP T cell in the tumor microenvironment. Further, these CD4 derived DP T cells upregulate CD8 lineage regulator Runx3 and cytolytic genes Gzmb, Gzmk, and Prf1 to become potent cytotoxic T cells. Alternatively, a subset of CD8 Pmel T cells differentiate into DP T cells characterized by the increased expression of CD4, ThPOK, and regulatory marker FoxP3 (figure 1). In addition, we utilized 10x single cell and ATAC sequencing to further characterize these divergent DP T cell populations among open repertoire T cells isolated from murine and human melanoma tumors.ConclusionsOur findings highlight the capability of single positive T cells to differentiate in response to antigen and local stimuli into novel T cell subsets with polyfunctional characteristics. The resulting cell subsets will potentially affect the tumor microenvironment in distinct ways. Our studies may inform therapeutic approaches to identify antigen specific T cells as well as innovative signaling pathways to target when genetically engineering T cells to optimize cytotoxic function in the setting of adoptive cell therapy.Ethics ApprovalThe human biospecimen analyses were approved by Memorial Sloan Kettering Cancer Center IRB #06-107ReferencesEllmeier W, Haust L & Tschismarov R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cell Mol Life Sci 2013;70:4537–4553.Luckey MA, et al. The transcription factor ThPOK suppresses Runx3 and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. Nature Immunology 2014; 15, 638–645.Bohner P, et al. Double positive CD4(+)CD8(+) T Cells are enriched in urological cancers and favor T Helper-2 polarization. Front Immunol 2019; 10, 622.Nascimbeni M, Shin E-C, Chiriboga L, Kleiner DE & Rehermann B. Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood 2004;104:478–486.Nishida K, et al. Clinical importance of the expression of CD4+CD8+ T cells in renal cell carcinoma. Int Immunol 2020;32:347–357.

scholarly journals Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice

1994 ◽  
Vol 14 (2) ◽  
pp. 1084-1094
Author(s):  
Z Hanna ◽  
C Simard ◽  
A Laperrière ◽  
P Jolicoeur
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cd8 T Cells ◽  
Transcription Initiation ◽  
Critical Role ◽  
Regulatory Elements ◽  
T Cell Subsets ◽  
Double Positive ◽  
Specific Expression

The CD4 protein plays a critical role in the development and function of the immune system. To gain more insight into the mechanism of expression of the human CD4 gene, we cloned 42.2 kbp of genomic sequences comprising the CD4 gene and its surrounding sequences. Studies with transgenic mice revealed that a 12.6-kbp fragment of the human CD4 gene (comprising 2.6 kbp of 5' sequences upstream of the transcription initiation site, the first two exons and introns, and part of exon 3) contains the sequences required to support the appropriate expression in murine mature CD4+ CD8- T cells and macrophages but not in immature double-positive CD4+ CD8+ T cells. Expression in CD4+ CD8+ T cells was found to require additional regulatory elements present in a T-cell enhancer fragment recently identified for the murine CD4 gene (S. Sawada and D. R. Littman, Mol. Cell. Biol. 11:5506-5515, 1991). These results suggest that expression of CD4 in mature and immature T-cell subsets may be controlled by distinct and independent regulatory elements. Alternatively, specific regulatory elements may control the expression of CD4 at different levels in mature and immature T-cell subsets. Our data also indicate that mouse macrophages contain the regulatory factors necessary to transcribe the human CD4 gene.

scholarly journals TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis

2019 ◽  
Vol 216 (7) ◽  
pp. 1682-1699 ◽  
Author(s):  
Lisa A. Mielke ◽  
Yang Liao ◽  
Ella Bridie Clemens ◽  
Matthew A. Firth ◽  
Brigette Duckworth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Double Positive ◽  
Cell Fate Decisions ◽  
Healthy Humans ◽  
Tc17 Cells

Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8+ T cell subsets. IL-17–producing CD8+ T cells isolated from healthy humans were also distinct from CD8+IL-17− T cells and enriched in pathways driven by MAF and RORγt. Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.

scholarly journals Pomalidomide Induces Expansion of Activated and Central Memory CD4+ and CD8+ T Cells in Vivo in Patients with and without HIV Infection

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4128-4128 ◽  
Author(s):  
Mark N. Polizzotto ◽  
Irini Sereti ◽  
Thomas S. Uldrick ◽  
Kathleen M. Wyvill ◽  
Stig M. R. Jensen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Kaposi Sarcoma ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Significant Difference

Abstract Background: Despite antiretroviral therapy (ART), people with HIV continue to exhibit immune deficits including failure to fully reconstitute CD4 T cell numbers and function, resulting in increased risks of tumors and infections and reduced response to vaccination. Pomalidomide, a derivative of thalidomide (IMID), has immunomodulatory properties that may be beneficial in this setting. We explored its impact on lymphocyte number and activation in patients with and without HIV treated within a prospective clinical trial for Kaposi sarcoma. Methods: Patients received pomalidomide 5mg orally for 21 days of 28 day cycles. Assessments were performed every 4 weeks for lymphocyte numbers, Kaposi sarcoma associated herpesvirus (KSHV/HHV8) viral load (VL) and HIV VL and at 8 weeks for T cell subsets and activation by immunophenotyping of peripheral blood mononuclear cells (PBMC). KSHV VL in PBMC and HIV VL in plasma were assayed by quantitative PCR; for HIV VL we used an ultrasensitive single copy assay. Changes from baseline were evaluated using the Wilcoxon signed rank test with P<0.005 considered significant given multiple comparisons. Differences in changes between the HIV infected and uninfected groups were evaluated using the Wilcoxon rank sum test. Study registered as NCT1495598. Results: 19 patients (12 HIV infected, 7 uninfected) median age 50 years (range 32-74) were studied. All with HIV were receiving ART for median 48 months (7-227), HIV VL 1.5 copies/mL (<0.5–37), and CD4 378 cells/µl (135–752). At week 4 and 8 of therapy we observed significant increases in CD4 and CD8 counts, with a decline in CD19 B cells and no change in NK cells or HIV VL. A transient increase in KSHV VL was seen at week 4, not sustained at week 8: Abstract 4128. Table 1ParameterBaseline (cells/µl unless noted)Change to Week 4 (Med, range)PChange to Week 8 (Med, range)PCD31143 (525–2305)+264 (-419–1524)0.0028+210 (-496–1455)0.0020CD4429 (135–1171)+107 (-87–650)0.0009+86 (-37–491)0.0015CD8495 (259–1529)+108 (-271–915)0.0085+155 (-495–834)0.0046NK184 (28–557)+30 (-130–117)0.52+2 (-174–127)0.98CD19139 (9–322)-47 (-117–76)0.0039-79 (-169–62)<0.0001KSHV VL 0 copies/PBMC (0–8750)+23 (-92–5250)0.00980 (-92–20850)0.31Plasma HIV VL (infected pts)1.5 copies/mL (<0.5–37)+0.3 (-1.5–3.0)0.75+0.75 (0–28)0.13 In addition, at week 8 both CD4 and CD8 T cells showed significant increases in activation (CD38+, HLADR+ and DR+/38+) and decreases in senescence (CD57+). Both also showed a significant shift towards increased central memory (CM) and away from naive (N) and effector (E) phenotypes, with no change in effector memory (EM) cells: Abstract 4128. Table 2CD4 SubsetsBaseline (%) (med, range)Absolute Change in % at Week 8 (med, range)PRO- 27+ (N)32.6 (13.3–76.5)-6.6 (-35.8–21.6)0.002RO+ 27+ (CM)41.9 (13.6–63.6)+6.4 (-15.5–32.5)0.027RO+ 27- (EM)16.7 (4.6–31.7)+1.7 (-7.2–21.0)0.28RO- 27- (E)3.3 (0.4–14.3)-1.5 (-5.7–0.3)0.000438+34.5 (11.2–67.3)+4.3 (-13.0–19.4)0.024HLA DR+8.9 (3.3–25.0)+8.3 (0.7–19.5)<0.000138+ DR+2.5 (0.6–11.7)+2 (-1.0–8.1)<0.000157+6.3 (0.6–26.6)-1.34 (-16.2–7.6)0.034CD8 SubsetsRO- 27+ (N)21.0 (9.7–70.4)-5.1 (-13.7–14.3)0.019RO+ 27+ (CM)17.1 (2.5–37.9)+8.1 (-8.4–18.6)0.0047RO+ 27- (EM)18.4 (4.6–40.8)+1.0 (-9.4–44.9)0.35RO- 27- (E)31.8 (4.1-63.7)-6.1 (-47.3–22.5)0.0138+33.4 (8.3–66.0)+19.9 (-0.8–40.6)<0.0001HLA DR+19.6 (5.0–46.4)+11.6 (-4.7–32.1)0.000138+ DR+8.0 (0.4–33.3)+8.5 (0.1–22.6)<0.000157+30.8 (2.9–72.9)-11.0 (-28.5–6.1)<0.0001 There were no significant changes in Ki67 or PD-1 expression in either CD4 or CD8 cells. There was no significant difference between HIV infected and uninfected patient groups in the observed effects on any parameter including cell number and phenotype. Conclusions: Pomalidomide induced significant increases in the number of CD4 and CD8 T cells and the proportion of activated and central memory cells and decreased senescence in both HIV infected and uninfected subjects. Effects were not explained by alterations in HIV viremia. The transient early rise in KSHV VL may reflect reactivation of latent infection and enhance immune killing of KSHV infected cells. This analysis sheds light on possible mechanisms of IMID activity in viral-associated tumors. As the first study of immune modulation by IMIDs in vivo in people with HIV it also suggests exploration of IMIDs to augment immune responsiveness in HIV and other immunodeficiencies is warranted. Disclosures Polizzotto: Celgene Corporation: Research Funding. Off Label Use: Pomalidomide for Kaposi sarcoma. Uldrick:Celgene Corporation: Research Funding. Zeldis:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Yarchoan:Celgene Corporation: Research Funding.

scholarly journals Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice.

1994 ◽  
Vol 14 (2) ◽  
pp. 1084-1094 ◽  
Author(s):  
Z Hanna ◽  
C Simard ◽  
A Laperrière ◽  
P Jolicoeur
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cd8 T Cells ◽  
Transcription Initiation ◽  
Critical Role ◽  
Regulatory Elements ◽  
T Cell Subsets ◽  
Double Positive ◽  
Specific Expression

The CD4 protein plays a critical role in the development and function of the immune system. To gain more insight into the mechanism of expression of the human CD4 gene, we cloned 42.2 kbp of genomic sequences comprising the CD4 gene and its surrounding sequences. Studies with transgenic mice revealed that a 12.6-kbp fragment of the human CD4 gene (comprising 2.6 kbp of 5' sequences upstream of the transcription initiation site, the first two exons and introns, and part of exon 3) contains the sequences required to support the appropriate expression in murine mature CD4+ CD8- T cells and macrophages but not in immature double-positive CD4+ CD8+ T cells. Expression in CD4+ CD8+ T cells was found to require additional regulatory elements present in a T-cell enhancer fragment recently identified for the murine CD4 gene (S. Sawada and D. R. Littman, Mol. Cell. Biol. 11:5506-5515, 1991). These results suggest that expression of CD4 in mature and immature T-cell subsets may be controlled by distinct and independent regulatory elements. Alternatively, specific regulatory elements may control the expression of CD4 at different levels in mature and immature T-cell subsets. Our data also indicate that mouse macrophages contain the regulatory factors necessary to transcribe the human CD4 gene.

scholarly journals Up-regulated Expression of Fas Antigen in Peripheral T cell Subsets in Patients with Myasthenia Gravis

2012 ◽  
Vol 35 (5) ◽  
pp. 294 ◽  
Author(s):  
Weihua Mai ◽  
Xingwei Liu ◽  
Yunping Fan ◽  
Hanwei Liu ◽  
Hai Yu Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Myasthenia Gravis ◽  
Cd8 T Cells ◽  
Corticosteroid Treatment ◽  
T Cell Subsets ◽  
Chinese Patients ◽  
Fas Antigen ◽  
Significant Difference ◽  
Regulated Expression

Purpose: Recent reports have linked various autoimmune diseases to defective Fas-mediated apoptosis or Fas expression. Here we aimed to determine whether Fas-mediated apoptosis is involved in the pathogenesis of myasthenia gravis (MG). Methods: The expression of Fas antigen in peripheral T cell subsets from 17 Chinese patients with MG and 13 healthy individuals was determined by flow cytometry, and its associations with clinical classification, thymus pathology, the concomitance with hyperthyroidism (HT) and corticosteroid treatment were investigated. Results: Compared with normal controls, a significantly up-regulated expression of Fas antigen was observed in the peripheral CD4+, CD4+CD8- and CD4-CD8- T cell subsets from patients with MG. Fas expression in CD4-CD8+ T cells of MG patients with normal thymus was significantly higher than that of patients with thymoma. Fas expressions in CD4+CD8+ T cells in MG patients with HT was significantly higher than controls and the ones without HT. Enhanced Fas expressions was found in CD4-CD8+ and CD4-CD8- T cells of MG patients with corticosteroid treatment, but no significant difference of Fas expression in peripheral T cells between patients with ocular MG (OMG) and general MG (GMG) was observed. Conclusion: Fas antigen may play a role in the pathogenesis of MG. It may be involved in the mechanisms of corticosteroid treatment, and with the occurrence of HT. OMG may represent a systemic disease, similar to that of GMG.

scholarly journals Clinical Observation of the Number of Lymphocytes and T Cell Subsets in Patients with COVID-19 at Different Stages

2020 ◽  
Author(s):  
Jing Bai ◽  
Hui Zhou ◽  
Bao-sheng Dai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
White Blood Cells ◽  
Peripheral Blood Lymphocytes ◽  
T Cell Subsets ◽  
Control Group ◽  
Cd8 Cells ◽  
Significant Difference ◽  
Severe Group

Abstract To explore the changes of lymphocytes and T cell subsets at different stages in patients with COVID-19. 86 patients with COVID-19 were enrolled, and the dynamic changes of peripheral blood lymphocytes and T cell subsets of CD3+, CD4+, and CD8+ were measured on admission, after treatment for1 week, 2 weeks, and before discharge. There were no significant differences in the number of white blood cells and lymphocytes between admission and 2 weeks after treatment or before discharge in severe patients. The counts of CD3+, CD4+, and CD8+ T cells decreased significantly on admission. After 2 weeks of treatment, the CD3+ counts were significantly higher than that on admission. The CD4+ and CD8+ counts increased significantly after 1 week of treatment, and went up remarkably before discharge compared with that on admission. There was no significant difference in the number of CD3+ cells between the mild group and the control group on admission, but it was significantly lower in the severe group than that in the control group and the mild group. The CD4+ and CD8+ counts decreased significantly in both mild and severe patients on admission, and increased significantly before discharge. At the time of discharge, the CD4+ counts in the severe and mild groups were still significantly lower than in the control group, but there was no significant difference in CD8+ counts among the three groups. The counts of CD3+,CD4+,and CD8+ T cells in the patients with COVID-19 is significantly correlated with the short-term prognosis, and is more sensitive than lymphocytes. In the earliest stage, the numbers of CD4+ and CD8+ cells are more sensitive to early reduction and faster to late recovery.

scholarly journals Differentiation of a CD4+/CD8αβ+ Double Positive T Cell Population From The CD8 Pool Is Sufficient To Mediate Graft-vs-Host Disease but not Graft-vs-Leukemia Effects

2022 ◽  
Author(s):  
Nicholas J Hess ◽  
David P Turicek ◽  
Kalyan Nadiminti ◽  
Amy Hudson ◽  
Peiman Hematti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Lymphoblastic Leukemia ◽  
T Cell Subsets ◽  
Double Positive ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Vs Host Disease ◽  
Xenogeneic Transplantation

Acute graft-vs-host disease (aGVHD) and tumor relapse remain the primary complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for malignant blood disorders. While post-transplant cyclophosphamide has reduced the overall prevalence and severity of aGVHD, relapse rates remain a concern. Thus, there remains a need to identify the specific human T cell subsets mediating GVHD pathology versus graft-versus-leukemia (GVL) effects. In xenogeneic transplantation studies using primary human cells from a variety of donors and tissue sources, we observed the development of a mature CD4+/CD8αβ+ double positive T cell (DPT) population in mice succumbing to lethal aGVHD but not in mice that failed to develop aGVHD. The presence of DPT, irrespective of graft source, was predictive of lethal GVHD as early as one week after xenogeneic transplantation. DPT co-express the master transcription factors of the CD8 and CD4 lineages, RUNX3 and THPOK respectively, and produce both cytotoxic and modulatory cytokines. To identify the origin of DPT, we transplanted isolated human CD4 or CD8 T cells, which in turn revealed that DPT only arise from the CD8 pool. Interestingly, re-transplantation of sorted CD8 T cells from GVHD mice did not reveal a second wave of DPT differentiation. Re-transplantation of flow-sorted DPT, CD8 or CD4 T cells from GVHD mice revealed that DPT are sufficient to mediate GVHD pathology but not GVL effects versus B-cell acute lymphoblastic leukemia. Lastly, we confirmed the presence and correlation of DPT with aGVHD pathology in a small cohort of allo-HSCT patients that developed grade 2-4 aGVHD in our clinic. Further understanding of DPT differentiation and pathology may lead to targeted prophylaxis and/or treatment regimens for aGVHD and potentially other human chronic inflammatory diseases.

scholarly journals 644 Tumor-mediated suppressive signaling and hypoxia supports altered chromatin landscapes that limit the transcriptional and functional potential of terminal T cell exhaustion

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A673-A673
Author(s):  
Rhodes Ford ◽  
Natalie Rittenhouse ◽  
Nicole Scharping ◽  
Paolo Vignali ◽  
Greg Delgoffe ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Histone Modifications ◽  
Cd8 T Cells ◽  
Tumor Hypoxia ◽  
T Cell Subsets ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

BackgroundCD8+ T cells are a fundamental component of the anti-tumor response; however, tumor-infiltrating CD8+ T cells (TIL) are rendered dysfunctional by the tumor microenvironment. CD8+ TIL display an exhausted phenotype with decreased cytokine expression and increased expression of co-inhibitory receptors (IRs), such as PD-1 and Tim-3. The acquisition of IRs mark the progression of dysfunctional TIL from progenitors (PD-1Low) to terminally exhausted (PD-1+Tim-3+). How the chromatin landscape changes during this progression has not been described.MethodsUsing a low-input ChIP-based assay called Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we have profiled the histone modifications at the chromatin of tumor-infiltrating CD8+ T cell subsets to better understand the relationship between the epigenome and the transcriptome as TIL progress towards terminal exhaustion.ResultsWe have identified two epigenetic characteristics unique to terminally exhausted cells. First, we have identified a unique set of genes, characterized by active histone modifications that do not have correlated gene expression. These regions are enriched for AP-1 transcription factor motifs, yet most AP-1 family factors are actively downregulated in terminally exhausted cells, suggesting signals that promote downregulation of AP-1 expression negatively impacts gene expression. We have shown that inducing expression of AP-1 factors with a 41BB agonist correlates with increased expression of these anticorrelated genes. We have also found a substantial increase in the number of genes that exhibit bivalent chromatin marks, defined by the presence of both active (H3K4me3) and repressive (H3K27me3) chromatin modifications that inhibit gene expression. These bivalent genes in terminally exhausted T cells are not associated with plasticity and represent aberrant hypermethylation in response to tumor hypoxia, which is necessary and sufficient to promote downregulation of bivalent genes.ConclusionsOur study defines for the first time the roles of costimulation and the tumor microenvironment in driving epigenetic features of terminally exhausted tumor-infiltrating T cells. These results suggest that terminally exhausted T cells have genes that are primed for expression, given the right signals and are the basis for future work that will elucidate that factors that drive progression towards terminal T cell exhaustion at the epigenetic level and identify novel therapeutic targets to restore effector function of tumor T cells and mediate tumor clearance.

scholarly journals Mitochondrial Dysfunction Associates With Acute T Lymphocytopenia and Impaired Functionality in COVID-19 Patients

2022 ◽  
Vol 12 ◽  
Author(s):  
Yufei Mo ◽  
Kelvin Kai-Wang To ◽  
Runhong Zhou ◽  
Li Liu ◽  
Tianyu Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mitochondrial Dysfunction ◽  
Cd8 T Cells ◽  
Functional Impairment ◽  
Cell Loss ◽  
Cd8 T Cell ◽  
Underlying Mechanism ◽  
T Cell Subsets ◽  
Effector Memory

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.

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