Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism

We have recently shown that expression of the enzyme indoleamine 2,3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic combination of the T cell–derived signals IFN-γ and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.

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PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

Frontiers in Immunology ◽

10.3389/fimmu.2021.695947 ◽

2021 ◽

Vol 12 ◽

Author(s):

Stephanie A. Amici ◽

Wissam Osman ◽

Mireia Guerau-de-Arellano

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Disease Severity ◽

Cell Cycle Progression ◽

T Cell Proliferation ◽

Cycle Progression ◽

Cyclin E1 ◽

Relapsing Remitting

Multiple Sclerosis (MS) is a debilitating central nervous system disorder associated with inflammatory T cells. Activation and expansion of inflammatory T cells is thought to be behind MS relapses and influence disease severity. Protein arginine N-methyltransferase 5 (PRMT5) is a T cell activation-induced enzyme that symmetrically dimethylates proteins and promotes T cell proliferation. However, the mechanism behind PRMT5-mediated control of T cell proliferation and whether PRMT5 contributes to diseases severity is unclear. Here, we evaluated the role of PRMT5 on cyclin/cdk pairs and cell cycle progression, as well as PRMT5’s link to disease severity in an animal model of relapsing-remitting MS. Treatment of T helper 1 (mTh1) cells with the selective PRMT5 inhibitor, HLCL65, arrested activation-induced T cell proliferation at the G1 stage of the cell cycle, suggesting PRMT5 promotes cell cycle progression in CD4+ T cells. The Cyclin E1/Cdk2 pair promoting G1/S progression was also decreased after PRMT5 inhibition, as was the phosphorylation of retinoblastoma. In the SJL mouse relapsing-remitting model of MS, the highest PRMT5 expression in central nervous system-infiltrating cells corresponded to peak and relapse timepoints. PRMT5 expression also positively correlated with increasing CD4 Th cell composition, disease severity and Cyclin E1 expression. These data indicate that PRMT5 promotes G1/S cell cycle progression and suggest that this effect influences disease severity and/or progression in the animal model of MS. Modulating PRMT5 levels may be useful for controlling T cell expansion in T cell-mediated diseases including MS.

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Adhesion of human T cells to antigen-presenting cells through SIRPβ2-CD47 interaction costimulates T-cell proliferation

Blood ◽

10.1182/blood-2004-07-2823 ◽

2005 ◽

Vol 105 (6) ◽

pp. 2421-2427 ◽

Cited By ~ 59

Author(s):

Laura Piccio ◽

William Vermi ◽

Kent S. Boles ◽

Anja Fuchs ◽

Carey A. Strader ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Antigen Presenting Cells ◽

Cell Types ◽

Orphan Receptor ◽

T Cell Proliferation ◽

Central Nervous Systems ◽

And Function ◽

Antigen Presenting

AbstractSignal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPα binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPβ1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPβ2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPβ2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPα, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPβ2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.

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Epigallocatechin-3-Gallate Directly Suppresses T Cell Proliferation through Impaired IL-2 Utilization and Cell Cycle Progression

Journal of Nutrition ◽

10.3945/jn.110.124743 ◽

2010 ◽

Vol 140 (8) ◽

pp. 1509-1515 ◽

Cited By ~ 26

Author(s):

Munkyong Pae ◽

Zhihong Ren ◽

Mohsen Meydani ◽

Fu Shang ◽

Simin Nikbin Meydani ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

T Cell ◽

Cell Cycle Progression ◽

T Cell Proliferation ◽

Cycle Progression

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Faculty Opinions recommendation of K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727203264.793528392 ◽

2017 ◽

Author(s):

Margot Thome

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

T Cell ◽

Cell Cycle Progression ◽

E3 Ligase ◽

T Cell Proliferation ◽

Cycle Progression

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K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

Nature Communications ◽

10.1038/ncomms14003 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 9

Author(s):

Zhenyue Hao ◽

Yi Sheng ◽

Gordon S. Duncan ◽

Wanda Y. Li ◽

Carmen Dominguez ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

T Cell ◽

Cell Cycle Progression ◽

E3 Ligase ◽

T Cell Proliferation ◽

Cycle Progression

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Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells

Journal of Experimental Medicine ◽

10.1084/jem.20020052 ◽

2002 ◽

Vol 196 (4) ◽

pp. 447-457 ◽

Cited By ~ 625

Author(s):

Peter Terness ◽

Thomas M. Bauer ◽

Lars Röse ◽

Christoph Dufter ◽

Andrea Watzlik ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

Cell Death ◽

Dendritic Cells ◽

T Cell ◽

Antigen Presenting Cells ◽

T Cell Proliferation ◽

Inhibition Of Proliferation ◽

Indoleamine 2,3 Dioxygenase ◽

Antigen Presenting

Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.

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CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

Molecular and Cellular Biology ◽

10.1128/mcb.25.17.7743-7757.2005 ◽

2005 ◽

Vol 25 (17) ◽

pp. 7743-7757 ◽

Cited By ~ 52

Author(s):

Kei Ohnuma ◽

Tadanori Yamochi ◽

Masahiko Uchiyama ◽

Kunika Nishibashi ◽

Satoshi Iwata ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Molecular Mechanisms ◽

Interleukin 1 ◽

Costimulatory Molecule ◽

Antigen Presenting Cells ◽

T Cell Proliferation ◽

Caveolin 1 ◽

Extracellular Region ◽

Antigen Presenting

ABSTRACT CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptor-associated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-κB. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigen-specific T-cell proliferation.

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PD-1 Signals Inhibit Cell Cycle Progression by Mediating Upregulation of Both KIP and INK Family of Cdk Inhibitors

Blood ◽

10.1182/blood.v116.21.585.585 ◽

2010 ◽

Vol 116 (21) ◽

pp. 585-585

Author(s):

Julia Brown ◽

Nikolaos Patsoukis ◽

Vassiliki A Boussiotis

Keyword(s):

Cell Cycle ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Cycle Progression ◽

S Phase ◽

Cdk Inhibitors ◽

Cycle Progression ◽

Smad3 Phosphorylation ◽

Cells Cultured

Abstract Abstract 585 The PD-1 pathway plays a critical role in the inhibition of T cell activation and the maintenance of T cell tolerance. PD-1 is expressed on activated T cells and limits T cell clonal expansion and effector function upon engagement with its ligands PD-L1 and PD-L2. PD-1 signals are vital for inhibition of autoimmunity whereas PD-1 ligation by PD-L1 and PD-L2 expressed on malignant cells has a detrimental effect on tumor-specific immunity. Furthermore, PD-1 signals result in T cell exhaustion in several chronic viral infections. The mechanism via which PD-1 signals mediate inhibition of T cell expansion is currently poorly understood. Here, we sought to determine the effects of PD-1 signals on mechanistic regulation of cell cycle progression mediated via TCR/CD3 and CD28 in primary human CD4+ T cells using anti-CD3/CD28 with or without agonist anti-PD-1 mAb conjugated to magnetic beads. Cell cycle analysis by ethynyl-deoxyuridine incorporation revealed that PD-1 induced blockade of cell cycle progression at the early G1 phase. To determine the molecular mechanisms underlying the blocked cell cycle progression we examined the expression and activation of cyclins and cdks and the regulation of cdk inhibitors that counterbalance the enzymatic activation of cyclin/cdk holoenzyme complexes. Our studies revealed that PD-1 mediated signals inhibited upregulation of Skp2, the SCF ubiquitin ligase that leads p27kip1 cdk inhibitor to ubiquitin-dependent degradation, and resulted in accumulation of p27kip1. Expression of cyclin E that is induced at the G1/S phase transition, and cyclin A that is synthesized during the S phase of the cell cycle, was dramatically reduced in the presence of PD-1 signaling. Strikingly, although expression of cdk4 and cdk2 was comparable between cells cultured in the presence or in the absence of PD-1, cdk2 enzymatic activation was significantly reduced in the presence of PD-1 signaling. Smad3 is a novel critical cdk substrate. Maximum cdk-mediated Smad3 phosphorylation occurs at the G1/S phase junction and requires activation of cdk2. Phosphorylation by cdk antagonizes TGF-β-induced transcriptional activity and antiproliferative function of Smad3 whereas impaired phosphorylation on the cdk-specific sites renders Smad3 more effective in executing its antiproliferative function. Based on those findings, we examined the effects of PD-1 signaling on Smad3 phosphorylation on cdk-specific and TGF-β-specific sites using site-specific phospho-Smad3 antibodies. Compared to anti-CD3/CD28 alone, culture in the presence of PD-1 induced impaired cdk2 activity, reduced levels of Smad3 phosphorylation on the cdk-specific sites and increased Smad3 phophorylation on the TGF-b-specific site. To determine whether the differential phosphorylation of Smad3 might differentially regulate Smad3 transcriptional activity in CD4+ T cells cultured in the presence versus the absence of PD-1, we examined expression of the INK family cdk4/6 inhibitor p15, a known downstream transcriptional target of Smad3. Expression of p15 was upregulated in CD4+ T cells cultured in the presence of PD-1 but not in cells cultured in the presence of CD3/CD28-coated beads alone. These results indicate that PD-1 signals inhibit cell cycle progression by mediating upregulation of both KIP and INK family of cdk inhibitors and Smad3 is a critical component of this mechanism, regulating blockade at the early G1 phase. Disclosures: No relevant conflicts of interest to declare.

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Antigen presentation by resting B cells. Radiosensitivity of the antigen-presentation function and two distinct pathways of T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.159.3.881 ◽

1984 ◽

Vol 159 (3) ◽

pp. 881-905 ◽

Cited By ~ 124

Author(s):

J D Ashwell ◽

A L DeFranco ◽

W E Paul ◽

R H Schwartz

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Antigen Presentation ◽

Cell Activation ◽

T Cell Proliferation ◽

B Cell Activation ◽

Antigen Presenting

In this report we have examined the ability of small resting B cells to act as antigen-presenting cells (APC) to antigen-specific MHC-restricted T cells as assessed by either T cell proliferation or T cell-dependent B cell stimulation. We found that 10 of 14 in vitro antigen-specific MHC-restricted T cell clones and lines and three of four T cell hybridomas could be induced to either proliferate or secrete IL-2 in the presence of lightly irradiated (1,000 rads) purified B cells and the appropriate foreign antigen. All T cell lines and hybridomas were stimulated to proliferate or make IL-2 by macrophage- and dendritic cell-enriched populations and all T cells tested except one hybridoma caused B cell activation when stimulated with B cells as APC. Furthermore, lightly irradiated, highly purified syngeneic B cells were as potent a source of APC for inducing B cell activation as were low density dendritic and macrophage-enriched cells. Lymph node T cells freshly taken from antigen-primed animals were also found to proliferate when cultured with purified B cells and the appropriate antigen. Thus, small resting B cells can function as APC to a variety of T cells. This APC function was easily measured when the cells were irradiated with 1,000 rads, but was greatly diminished or absent when they were irradiated with 3,300 rads. Thus, the failure of some other laboratories to observe this phenomenon may be the result of the relative radiosensitivity of the antigen-presenting function of the B cells. In addition, this radiosensitivity allowed us to easily distinguish B cell antigen presentation from presentation by the dendritic cell and macrophage, as the latter was resistant to 3,300 rads. Finally, one T cell clone that failed to proliferate when B cells were used as APC was able to recruit allogeneic B cells to proliferate in the presence of syngeneic B cells and the appropriate antigen. This result suggests that there are at least two distinct pathways of activation in T cells, one that leads to T cell proliferation and one that leads to the secretion of B cell recruitment factor(s).

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