The effect of the ratio of CD4 + to CD8 + T-cells on radiation-induced apoptosis in human lymphocyte subpopulations

Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.

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CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽

10.1182/blood.v96.1.195.013k51_195_202 ◽

2000 ◽

Vol 96 (1) ◽

pp. 195-202 ◽

Cited By ~ 1

Author(s):

Masaki Tateyama ◽

Naoki Oyaizu ◽

Thomas W. McCloskey ◽

Soe Than ◽

Savita Pahwa

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Interleukin 2 ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Cross Linking ◽

Induced Apoptosis ◽

Hiv 1

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

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Increased CD95/Fas-Induced Apoptosis of HIV-Specific CD8+ T Cells

Immunity ◽

10.1016/s1074-7613(01)00246-1 ◽

2001 ◽

Vol 15 (6) ◽

pp. 871-882 ◽

Cited By ~ 125

Author(s):

Yvonne M Mueller ◽

Stephen C De Rosa ◽

Justin A Hutton ◽

James Witek ◽

Mario Roederer ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Induced Apoptosis

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THE EXPRESSION OF CD11A BUT NOT CD45RA CORRELATES WITH CD95 (FAS/APO-1) EXPRESSION, ENHANCED ACTIVATION INDUCED APOPTOSIS AND CD55 EXPRESSION IN HUMAN CD8 T CELLS

Biochemical Society Transactions ◽

10.1042/bst024619sa ◽

1996 ◽

Vol 24 (4) ◽

pp. 619S-619S

Author(s):

C. Höflich ◽

W.-D. Döcke ◽

H.-D. Volk

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Induced Apoptosis

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ANTIBODIES WHICH TARGET THE COMMON CYTOKINE RECEPTOR GAMMA (γc) CHAIN ENHANCE ACTIVATION-INDUCED APOPTOSIS OF ALLOSPECIFIC CD8+ T CELLS

Transplantation Journal ◽

10.1097/00007890-199904150-00088 ◽

1999 ◽

Vol 67 (7) ◽

pp. S21 ◽

Cited By ~ 1

Author(s):

Z Dai ◽

A Arakelov ◽

M. Wagener ◽

B. T. Konieczny ◽

F G Lakkis

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cytokine Receptor ◽

The Common ◽

Induced Apoptosis

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Circulating immune markers predict the therapeutic effect in primary lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21203 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21203-e21203

Author(s):

Liangliang Xu ◽

Jitian Zhang ◽

Li Yang ◽

Guangqiang Shao ◽

Taiyang Liuru ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Blood Lymphocyte ◽

Lymphocyte Subpopulations ◽

Significant Difference

e21203 Background: Radiotherapy (RT), surgical resection (SR), and immunotherapy (IT) as main therapies in lung cancer have either suppressive or stimulatory effects on the immune system. It’s still unclear the mechanism involved in the systemic changes of immune cells in the blood. Peripheral blood lymphocyte subpopulations were useful markers for evaluating immune response in tumor patients. Hence, we aimed to systematically investigate the alteration of lymphocyte subpopulations during the local therapies to evaluate antitumor treatment effects. Methods: Blood samples were obtained EDTA coated tubes and then centrifuged gently for white blood cell separation. The white blood cells in 10% DMSO and 90% FBS were frozen slowly in -80°C refrigerator. The following fluorochrome-conjugated surface and nuclear antibodies were used in the lymphocyte subtyping: CD11b, CD45, CD19, CD3, CD56, CD4, CD8a, CD25,CD127 and FOXP3. The staining cells were detected in the BD FACS machine and data were analyzed by the paired T-test. The percentage of Lymphocytes, Myeloid cells, B cells, T cells, Treg, CD8+ T cells, CD4+ T cells, NK cells, and NKT were examined. Results: Between July 2019 and January 2020, a total of 176 patients eligible, including 135 RT patients and 29 SR patients,12 IT patients, with both blood collection with both Pre, During and End therapies. Before local therapies, the percentage of total T cells in the RT group was significantly higher than SR (RT v.s SR mean:64.1 v.s 55.3, P = 0.02) while CD8+ T cells (RT v.s SR mean:28.2 v.s 34.5, P = 0.04)and Tregs (RT v.s SR mean:0.0 v.s 0.1, P = 0.055) were lower. The baseline level of T cells and their subtypes showed a significant difference in these two group patients. After local therapies, myeloid cells, lymphocytes, CD4+ T cells, CD8+ T cells, NK cells were significant different. There is no significant difference due to the smaller number of IT patients. In the RT group, lymphocytes (Pre-RT v.s End-RT mean:75.2 v.s 54.3, P = 0.004) and B cells (Pre-RT v.s End-RT mean:12.6 v.s 8.0, P = 0.03) were significantly decreased while other subpopulations didn’t show any significant difference after RT. Interestingly, in the SR group, there was a significant increase in CD4+ T cells (mean:59.0 v.s 62.1, p = 0.02) a trend of reduction in CD8+ T cells (mean:34.5 v.s 32.0, p = 0.055) after SR. In addition, there was an increased trend of Tregs after IT. Conclusions: There are some different patterns of distribution in subtypes of leukocytes in operable and inoperable patients and between different therapies. All RT, SR and IT changed the distribution of peripheral blood lymphocyte subpopulations. Further validation study is warranted to validate our findings particularly in circulating lymphocytes and B cells as a marker to evaluate immune status after RT, CD4+ T cells and CD8+ T cells after SR, Tregs after IT, as well as their relationship with tumor microenvironment and implication for personalized care.

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JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation

Blood ◽

10.1182/blood.2020006075 ◽

2020 ◽

Vol 136 (6) ◽

pp. 657-668 ◽

Cited By ~ 7

Author(s):

Lauren K. Meyer ◽

Katherine C. Verbist ◽

Sabrin Albeituni ◽

Brooks P. Scull ◽

Rachel C. Bassett ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Ex Vivo ◽

Lymphoblastic Leukemia ◽

Immune System Activation ◽

Stat Signaling ◽

Induced Apoptosis ◽

Stat Pathway

Abstract Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.

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