Interleukin-2 immunotherapy exerts a differential effect on CD4 and CD8 T cell dynamics

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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Interleukin 2 induces CD8+ T cell-mediated suppression of human immunodeficiency virus replication in CD4+ T cells and this effect overrides its ability to stimulate virus expression.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.92.24.10985 ◽

1995 ◽

Vol 92 (24) ◽

pp. 10985-10989 ◽

Cited By ~ 48

Author(s):

A. L. Kinter ◽

S. M. Bende ◽

E. C. Hardy ◽

R. Jackson ◽

A. S. Fauci

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Cell ◽

Virus Replication ◽

Cd4 T Cells ◽

Interleukin 2 ◽

Cd8 T Cell ◽

Human Immunodeficiency Virus Replication ◽

Immunodeficiency Virus ◽

Virus Expression

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The differential effect of prednisolone on various T-cell subsets and their expression of interleukin 2 (IL2) receptors

International Journal of Immunopharmacology ◽

10.1016/0192-0561(85)90370-4 ◽

1985 ◽

Vol 7 (3) ◽

pp. 370

Author(s):

Sue Y. Tsang ◽

Marvin R. Garovoy ◽

Leslie Z. Benet

Keyword(s):

T Cell ◽

Differential Effect ◽

Interleukin 2 ◽

T Cell Subsets

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Ecto-5′-Nucleotidase (CD73) Regulates the Survival of CD8+ T Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.647058 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mariana V. Rosemblatt ◽

Brian Parra-Tello ◽

Pedro Briceño ◽

Elizabeth Rivas-Yáñez ◽

Suat Tucer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Interleukin 2 ◽

Cd8 T Cell ◽

Antigenic Stimulation ◽

T Cell Subsets ◽

Limited Information ◽

Α Chain ◽

The Impact

Ecto-5′-nucleotidase (CD73) is an enzyme present on the surface of tumor cells whose primary described function is the production of extracellular adenosine. Due to the immunosuppressive properties of adenosine, CD73 is being investigated as a target for new antitumor therapies. We and others have described that CD73 is present at the surface of different CD8+ T cell subsets. Nonetheless, there is limited information as to whether CD73 affects CD8+ T cell proliferation and survival. In this study, we assessed the impact of CD73 deficiency on CD8+ T cells by analyzing their proliferation and survival in antigenic and homeostatic conditions. Results obtained from adoptive transfer experiments demonstrate a paradoxical role of CD73. On one side, it favors the expression of interleukin-7 receptor α chain on CD8+ T cells and their homeostatic survival; on the other side, it reduces the survival of activated CD8+ T cells under antigenic stimulation. Also, upon in vitro antigenic stimulation, CD73 decreases the expression of interleukin-2 receptor α chain and the anti-apoptotic molecule Bcl-2, findings that may explain the reduced CD8+ T cell survival observed in this condition. These results indicate that CD73 has a dual effect on CD8+ T cells depending on whether they are subject to an antigenic or homeostatic stimulus, and thus, special attention should be given to these aspects when considering CD73 blockade in the design of novel antitumor therapies.

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Interleukin-15 Triggers Activation and Growth of the CD8 T-Cell Pool in Extravascular Tissues of Patients With Acquired Immunodeficiency Syndrome

Blood ◽

10.1182/blood.v90.3.1115 ◽

1997 ◽

Vol 90 (3) ◽

pp. 1115-1123 ◽

Cited By ~ 39

Author(s):

Carlo Agostini ◽

Livio Trentin ◽

Rosaria Sancetta ◽

Monica Facco ◽

Cristina Tassinari ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Cd8 T Cells ◽

Biological Activities ◽

Interleukin 2 ◽

Cd8 T Cell ◽

Tissue Growth ◽

Activation Markers ◽

Accessory Function

Abstract The impairment of interleukin-2 (IL-2) production occurs very early after human immunodeficiency virus (HIV) infection as a consequence of the quantitative depletion of Th1 cells. Despite the shift in cytokine production, most individuals develop an oligoclonal expansion of major histocompatibility complex restricted, HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in different organs, suggesting that other cytokines replace IL-2 in initiating the tissue infiltration of CD8+ T cells. In this study we show that IL-15, a product of monocyte-macrophages and non-T cells and which has overlapping biological activities with IL-2, is involved in local cell networks accounting for the activation and expansion of CD8+ T-cell pools in a highly affected organ, ie, the lung. IL-15 induced proliferation of T cells obtained from the lower respiratory tract of HIV-infected patients with T-cell alveolitis and severe depletion of CD4+ T cells. Lung lymphocytes were CD45R0+/CD8+ T cells spontaneously expressing activation markers (CD69 and HLA-DR) and equipped with the receptorial subunits which bind IL-15, notably the β and γ chains of the IL-2 receptor (IL-2R) and the recently identified IL-15 binding-protein termed IL-15Rα. Similar phenotypic findings were obtained after incubation of normal T cells with IL-15, which induced CD8+ T cells to express activation markers and to proliferate. The block of the IL-2Rβ/IL-2Rγ complex with specific monoclonal antibodies abolished the T-cell stimulatory activity of IL-15 while the combination of IL-15 and tumor necrosis factor-α upregulated the proliferative response of lung T lymphocytes. The hypothesis that the tissue growth of lung CD8+ lymphocytes may involve cytokines produced from cells other than T lymphocytes was confirmed by the evidence that pulmonary macrophages expressed high levels of IL-15 and that anti–IL-15 antibodies inhibited the accessory function of alveolar macrophages on mitogen-induced CD8+ T-cell proliferation. Together, these results suggest that macrophage-derived cytokines produced at sites of T-cell infiltration play a role in the activation of HIV-specific CD8+ T-cell–mediated immune response.

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Determinants of hepatic effector CD8+ T cell dynamics

Journal of Hepatology ◽

10.1016/j.jhep.2016.07.011 ◽

2017 ◽

Vol 66 (1) ◽

pp. 228-233 ◽

Cited By ~ 12

Author(s):

Alexandre Pierre Benechet ◽

Matteo Iannacone

Keyword(s):

T Cell ◽

Cd8 T Cell ◽

Cell Dynamics

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Maintenance of viral suppression in HIV-1–infected HLA-B*57+ elite suppressors despite CTL escape mutations

Journal of Experimental Medicine ◽

10.1084/jem.20052319 ◽

2006 ◽

Vol 203 (5) ◽

pp. 1357-1369 ◽

Cited By ~ 196

Author(s):

Justin R. Bailey ◽

Thomas M. Williams ◽

Robert F. Siliciano ◽

Joel N. Blankson

Keyword(s):

T Cell ◽

Viral Suppression ◽

Selective Pressure ◽

De Novo ◽

Interleukin 2 ◽

Cd8 T Cell ◽

Plasma Virus ◽

Low Level ◽

Ctl Escape ◽

Elite Suppressors

Rare human immunodeficiency virus 1–infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57–restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57–restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon-γ responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57–restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.

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