Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

AbstractInterleukin 2 (IL-2) is a key homeostatic cytokine, with potential therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical application has been hampered by pleiotropic functionality and wide-spread receptor expression, with unexpected adverse events during trials. To characterize the IL-2 homeostatic network, we developed a novel mouse strain allowing IL-2 production to be diverted. Rewiring of IL-2 production to diverse leukocyte sources allowed the identification of contextual influences over IL-2 impact. Network analysis identified a priority access for Tregs, and a competitive fitness cost induced among both Tregs and conventional CD4 T cells for IL-2 production. CD8 T cells and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified the Treg circuit, while IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells. The former was associated with an unexpected concentration of rare CD8+ Tregs in B cell zones, while the latter drove a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain unexpected adverse effects observed during clinical trials of exogenous IL-2. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.Graphical abstract

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Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT

Frontiers in Immunology ◽

10.3389/fimmu.2020.593863 ◽

2020 ◽

Vol 11 ◽

Author(s):

Mahinbanu Mammadli ◽

Weishan Huang ◽

Rebecca Harris ◽

Aisha Sultana ◽

Ying Cheng ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lymphoblastic Leukemia ◽

Interleukin 2 ◽

Treatment Strategies ◽

Receptor Expression ◽

Hematopoietic Stem ◽

Target Organs ◽

Donor T Cells ◽

Inducible T Cell Kinase

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

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Diltiazem inhibits transferrin receptor expression and causes G1 arrest in normal and neoplastic T cells

Molecular and Cellular Biology ◽

10.1128/mcb.6.12.4244-4250.1986 ◽

1986 ◽

Vol 6 (12) ◽

pp. 4244-4250

Author(s):

L M Neckers ◽

S Bauer ◽

R C McGlennen ◽

J B Trepel ◽

K Rao ◽

...

Keyword(s):

T Cells ◽

Transferrin Receptor ◽

Interleukin 2 ◽

Receptor Expression ◽

Calcium Flux ◽

G1 Arrest ◽

Receptor Mrna ◽

Interleukin 2 Receptor ◽

Transferrin Receptor Expression ◽

Malignant T Cells

Transferrin receptor expression is essential for the proliferation of both normal and malignant T cells. While transferrin receptor expression in normal T cells is tightly coupled to interleukin-2 receptor expression, transferrin receptor expression in malignant cells is usually constitutive and is released from this constraint. Temporally, the appearance of these membrane receptors is preceded by changes in the expression of the proto-oncogenes c-myc and c-myb. In addition, although an increase in the level of intracellular free calcium occurs early in the sequence of T-cell activation, the activation events dependent on this calcium flux have not been resolved. In the present study we report that diltiazem, an ion channel-blocking agent that inhibits calcium influx, arrested the growth in vitro of both normal and malignant human T cells in the G1 phase of the cell cycle. However, diltiazem did not inhibit the expression of c-myc or interleukin-2 receptor mRNA and protein in normal mitogen-activated T cells or the constitutive expression of c-myc and c-myb mRNA in malignant T cells (T acute lymphoblastic leukemia cells). In contrast, diltiazem prevented the induction of transferrin receptor (mRNA and protein) in normal T cells and caused a progressive loss of transferrin receptor (mRNA and protein) in malignant T cells. These data demonstrate that diltiazem can dissociate several growth-related processes normally occurring in G1 and thereby disrupt the biochemical cascade leading to cell proliferation.

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Abstract 033: Differential Vasopressin Receptor Expression on CD4+ T Cells from Mouse and Human Preeclamptic Pregnancies

Hypertension ◽

10.1161/hyp.68.suppl_1.033 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Sabrina M Scroggins ◽

Donna A Santillan ◽

Jenna M Peterson ◽

Nicole A Pearson ◽

Jeremy A Sandgren ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Immune Modulation ◽

Inflammatory Cytokine ◽

Mononuclear Cells ◽

Cytokine Production ◽

Cell Activity ◽

Tissue Bank ◽

Receptor Expression ◽

Inflammatory Cytokine Production

The pathogenesis of preeclampsia (PreE) involves the failure of the maternal immune system to normally tolerate the pregnancy. Inflammatory cytokines are elevated in PreE-affected women with a concurrent decrease in anti-inflammatory cytokine production. Consistent with what other groups have observed in mouse models of hypertension during pregnancy and in human PreE-affected pregnancies, we observed increased inflammatory cytokine production and CD4+ T helper populations in our chronic infusion of vasopressin (AVP) mouse model of PreE. The mechanisms of immune modulation by AVP have not been elucidated. As increased T cell activity is involved in the development of PreE, the objective of this study was to investigate if CD4+ T cells express AVP receptors. Splenic CD4+ T cells were negatively purified from C57BL/6J saline and AVP-infused (24 ng/hour) dams. Expression of AVP receptors (AVPR) 1a, 1b, 2, and the aminopeptidase LNPEP (catalyzes AVP degradation) was determined via qPCR. Raw cycle threshold (Ct) values were normalized (ΔCt) against the 18S rRNA endogenous control. Mouse CD4+ T cells express all AVP receptors and LNPEP. By ANOVA, AVPR2 is the highest expressed receptor in CD4+ T cells from saline (N=7, p=0.002) and AVP-infused (N=10, p<0.0001) dams. Human maternal mononuclear cells, obtained from the University of Iowa Maternal-Fetal Tissue Bank (IRB #200910784) from control and PreE-affected women, were similarly analyzed. As in mouse CD4+ T cells, human control (N=27, p<0.0001) and PreE-affected (N=26, p<0.0001) CD4+ T cells most highly expressed AVPR2. AVPR1a was also highly expressed while AVPR1b was the least expressed. CD4+ T cells isolated from human PreE-affected women expressed significantly lower AVPR1a (10.0±0.3 N=27 vs. 11.1±0.2 N=0.23, p=0.009) and increased LNPEP (17.2±0.5 N=27 vs. 15.1±0.3 N=26, p=0.001) than controls. Here, we demonstrate CD4+ T cells, both mouse and human, express AVP receptors and that 1a and 2 are highest expressed. Although the actions of AVP on the vasculature are primarily mediated through AVPR1a, these data suggest AVP may differentially act through AVPR1a to mediate immune responses during PreE.

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Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen).

Journal of Experimental Medicine ◽

10.1084/jem.161.6.1513 ◽

1985 ◽

Vol 161 (6) ◽

pp. 1513-1524 ◽

Cited By ~ 183

Author(s):

T Hara ◽

S M Fu ◽

J A Hansen

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Interleukin 2 ◽

Cell Subset ◽

Receptor Expression ◽

T Cell Proliferation ◽

Activation Pathway

In previous studies (17-21), monoclonal antibody (mAb) 9.3 has been shown to react with a major population of human T cells, which include T4+ helper/inducer T cells and T8+ cytotoxic T cells. In this investigation, mAb 9.3 was shown to precipitate a disulfide-bonded dimer of a 44 kD polypeptide. Comodulation experiments showed that this molecule is not linked to T3/Ti or T11 antigens. mAb 9.3 was capable of inducing T cell proliferation in the presence of 12-o-tetradecanoyl phorbol-13-acetate (TPA). This effect was monocyte-independent. T cell activation with mAb 9.3 and TPA was associated with increases in interleukin 2(IL-2) receptor expression and IL-2 secretion. mAb 9.3 did not activate T cells, even with the addition of IL-1 or IL-2. Modulation of the T3 complex did not abolish mAb 9.3-induced T cell proliferation in the presence of TPA. These results suggest that the 9.3 antigen may serve as a receptor for an activation pathway restricted to a T cell subset.

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INHIBITION OF INTERLEUKIN 2 RECEPTOR EXPRESSION IN NORMAL HUMAN T CELLS BY CYCLOSPORINE

Transplantation Journal ◽

10.1097/00007890-199201000-00030 ◽

1992 ◽

Vol 53 (1) ◽

pp. 146-150 ◽

Cited By ~ 13

Author(s):

BAOGUI LI ◽

PRABODH K. SEHAJPAL ◽

AJIT SUBRAMANIAM ◽

ANTONIO JOSEPH ◽

KURT H. STENZEL ◽

...

Keyword(s):

T Cells ◽

Interleukin 2 ◽

Receptor Expression ◽

Interleukin 2 Receptor ◽

Human T Cells ◽

Normal Human

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CCCTC-Binding Factor Translates Interleukin 2- and α-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs

Immunity ◽

10.1016/j.immuni.2017.07.015 ◽

2017 ◽

Vol 47 (2) ◽

pp. 251-267.e7 ◽

Cited By ~ 29

Author(s):

Danielle A. Chisolm ◽

Daniel Savic ◽

Amanda J. Moore ◽

Andre Ballesteros-Tato ◽

Beatriz León ◽

...

Keyword(s):

T Cells ◽

Interleukin 2 ◽

Metabolic Changes ◽

Binding Factor ◽

Context Dependent

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Proliferation Response to Interleukin-2 and Jak/Stat Activation of T Cells Immortalized by Human T-Cell Lymphotropic Virus Type 1 Is Independent of Open Reading Frame I Expression

Journal of Virology ◽

10.1128/jvi.73.11.9642-9649.1999 ◽

1999 ◽

Vol 73 (11) ◽

pp. 9642-9649 ◽

Cited By ~ 31

Author(s):

Nathaniel D. Collins ◽

Celine D’Souza ◽

Björn Albrecht ◽

Michael D. Robek ◽

Lee Ratner ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Virus Type ◽

Interleukin 2 ◽

Receptor Expression ◽

Open Reading Frame ◽

Reading Frame ◽

Human T Cell

ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1), a complex retrovirus, encodes a hydrophobic 12-kD protein from pX open reading frame (ORF) I that localizes to cellular endomembranes and contains four minimal SH3 binding motifs (PXXP). We have demonstrated the importance of ORF I expression in the establishment of infection and hypothesize that p12I has a role in T-cell activation. In this study, we tested interleukin-2 (IL-2) receptor expression, IL-2-mediated proliferation, and Jak/Stat activation in T-cell lines immortalized with either wild-type or ORF I mutant clones of HTLV-1. All cell lines exhibited typical patterns of T-cell markers and maintained mutation fidelity. No significant differences between cell lines were observed in IL-2 receptor chain (α, β, or γc) expression, in IL-2-mediated proliferation, or in IL-2-induced phosphorylated forms of Stat3, Stat5, Jak1, or Jak3. The expression of ORF I is more likely to play a role in early HTLV-1 infection, such as in the activation of quiescent T cells in vivo.

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The T-cell CD2 determinant mediates inhibition of erythropoiesis by the lymphokine cascade

Blood ◽

10.1182/blood.v72.2.770.770 ◽

1988 ◽

Vol 72 (2) ◽

pp. 770-775 ◽

Cited By ~ 4

Author(s):

S Burdach ◽

M Shatsky ◽

B Wagenhorst ◽

L Levitt

Keyword(s):

T Cells ◽

T Cell ◽

Interleukin 2 ◽

Receptor Expression ◽

Isotype Control ◽

Isotype Control Antibody ◽

Dependent Inhibition ◽

Neutralizing Monoclonal Antibody ◽

Dose Dependent Inhibition

Abstract We examined the role of the T-cell antigen CD2 in the regulation of erythropoiesis by the lymphokine cascade. T-cell interleukin-2 (IL-2) receptors (p55) were induced via triggering of the antigen receptor- associated CD3 epitope. Before CD3 triggering T cells were preincubated with a CD2-blocking (Leu-5b) or isotype control antibody. T-cell pellets were employed during incubation to facilitate interaction between T-cell LFA-3 and CD2. CD2 blockade caused a 66% to 79% inhibition of p55 expression after three to six days of culture with IL- 2. Next we assessed the effect of CD2 blockade on IL-2. Next we assessed the effect of CD2 blockade on IL-2-induced inhibition of BFU-E in autologous cocultures containing CD3-triggered T cells. IL-2 caused a dose-dependent inhibition (52% to 92%) of BFU-E in the presence but not in the absence of CD3-triggered T cells. T-cell CD2 blockade prior to CD3 triggering caused a 65% to 87% abrogation of IL-2-induced inhibition of BFU-E at 10 to 10(2) U/mL IL-2. Preincubation of CD3- triggered T cells with isotype control antibody had no effect on IL-2- induced erythroid inhibition. Day 3 supernatants from CD3-triggered T cells or CD2-blocked, CD3-triggered T cells established in the presence of IL-2 were next assessed for modulation of BFU-E. CD3-triggered T- cell supernatants caused a 77% +/- 9% inhibition of BFU-E. Blockade of CD2 caused a 95% abrogation of T-cell-mediated BFU-E inhibition. In addition, CD2 blockade reduced interferon-gamma (IF gamma) release (84 to 128 U/mL) from CD3-triggered T cells by 81% at day 3 of culture. In control experiments, the addition of IF gamma-neutralizing monoclonal antibody to CD3-triggered T-cell supernatant established in the presence of IL-2 caused 75% abrogation of IL-2 inhibition of BFU-E. We conclude that blockade of the CD2 T-cell determinant induces down modulation of (a) T-cell p55 IL-2 receptor expression, (b) IL-2-induced inhibition of BFU-E, and (c) IL-2-induced marrow T-cell IF gamma release. These data suggest that the T-cell CD2 determinant can exert a regulatory effect on the control of erythropoiesis by the lymphokine cascade.

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