Human natural killer cells exposed to IL-2, IL-12, IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells

Abstract Dendritic cells (DCs) play a crucial role in naive T-cell priming. Recent data suggested that natural killer (NK) cells can influence the capability of DCs to promote Th1 polarization. This regulatory function is primarily mediated by cytokines released in the microenvironment during inflammatory responses involving NK cells. In this study, we show that human NK cells exposed for short time to interleukin (IL)–12, IL-2, or IL-18, promote distinct pathways of Th1 priming. IL-12– or IL-2–conditioned NK cells induce maturation of DCs capable of priming IFN-γ–producing Th1 cells. On the other hand, IL-18–conditioned NK cells induce Th1 polarization only when cocultured with both DCs and T cells. In this case, IL-2 released by T cells and IL-12 derived from DCs during the priming process promote interferon (IFN)–γ production. In contrast, when NK cells are exposed to IL-4, nonpolarized T cells releasing only low levels of IL-2 are generated. Thus, the prevalence of IL-12, IL-2, IL-18, or IL-4 at inflammatory sites may differentially modulate the NK-cell interaction with DCs, leading to different outcomes in naive T-cell polarization.

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The lymphoid chemokine CCL21 costimulates naïve T cell expansion and Th1 polarization of non-regulatory CD4+ T cells

Cellular Immunology ◽

10.1016/j.cellimm.2004.12.006 ◽

2004 ◽

Vol 231 (1-2) ◽

pp. 75-84 ◽

Cited By ~ 75

Author(s):

Kenneth Flanagan ◽

Dorota Moroziewicz ◽

Heesun Kwak ◽

Heidi Hörig ◽

Howard L. Kaufman

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Expansion ◽

T Cell Expansion ◽

Th1 Polarization ◽

Naïve T Cell ◽

Naive T Cell

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Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion

Blood ◽

10.1182/blood-2003-05-1408 ◽

2003 ◽

Vol 102 (10) ◽

pp. 3668-3674 ◽

Cited By ~ 33

Author(s):

Maria C. Kuppner ◽

Anabel Scharner ◽

Valeria Milani ◽

Christoph von Hesler ◽

Katharina E. Tschöp ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Nk Cells ◽

Cell Function ◽

Nk Cell ◽

Human Monocyte ◽

Glutathione Depletion ◽

Intracellular Glutathione ◽

Ifn Γ

AbstractIfosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon-γ (IFN-γ) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-γ. The decrease in allostimulatory capacity and in IFN-γ and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function. (Blood. 2003;102: 3668-3674)

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Memory CD4 T Cells Induce Selective Expression of IL-27 in CD8+ Dendritic Cells and Regulate Homeostatic Naive T Cell Proliferation

The Journal of Immunology ◽

10.4049/jimmunol.1101908 ◽

2011 ◽

Vol 188 (1) ◽

pp. 230-237 ◽

Cited By ~ 4

Author(s):

Jeong-su Do ◽

Anabelle Visperas ◽

Keunhee Oh ◽

Stephen A. Stohlman ◽

Booki Min

Keyword(s):

Cell Proliferation ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Proliferation ◽

Selective Expression ◽

Memory Cd4 T Cells ◽

Naïve T Cell ◽

Naive T Cell

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Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)–producing dendritic cells: too much ado about IDO?

Blood ◽

10.1182/blood-2004-06-2103 ◽

2005 ◽

Vol 105 (6) ◽

pp. 2480-2486 ◽

Cited By ~ 66

Author(s):

Peter Terness ◽

Jing-Jing Chuang ◽

Thomas Bauer ◽

Lucian Jiga ◽

Gerhard Opelz

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cell Response ◽

Human Monocyte ◽

T Cell Response ◽

Regulatory Function ◽

Blood Monocytes ◽

Indoleamine 2,3 Dioxygenase ◽

Ifn Γ

AbstractAlthough dendritic cells (DCs) strongly stimulate the immune response, they can also induce unresponsiveness. Recently, a human monocyte-derived DC subpopulation was described that constitutively expresses indoleamine 2,3-dioxygenase (IDO). These DCs were defined as nonadherent CD123+/CC chemokine receptor 6+ (CCR6+) cells that suppress the allogeneic T-cell response. In the present study, we generated nonadherent, mature DCs from human blood monocytes. As expected, in addition to the classic markers, these cells expressed CD123 and CCR6. Reverse transcription–polymerase chain reaction (RT-PCR), however, did not show IDO gene transcription, nor did we detect enzymatic IDO activity. Treating the cells with interferon-γ (IFN-γ) resulted in significant IDO production. Subsequently, we studied the regulatory properties of IDO-producing DCs on autologous and allogeneic T-cell responses. Neither OKT3-stimulated T cells of healthy donors nor myelin basic protein (MBP)–specific T cells of patients with multiple sclerosis (MS) were suppressed by autologous IDO DCs. However, whereas IDOneg DCs supported further stimulation of preactivated MBP-specific T cells of an MS patient, IDOpos DCs had lost this capacity. The allogeneic T-cell response was only marginally suppressed by IDO DCs. Our findings show that nonadherent CD123+/CCR6+ human DCs do not constitutively express IDO, and, even if they express the enzyme after IFN-γ treatment, they possess only limited T-cell regulatory function.

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Histamine enhances HIV-1-induced modulation of dendritic cells to skew naïve T cell differentiation toward regulatory T cells

Virology ◽

10.1016/j.virol.2013.04.009 ◽

2013 ◽

Vol 442 (2) ◽

pp. 163-172 ◽

Cited By ~ 7

Author(s):

Rong-Rong Zhai ◽

Ai-Ping Jiang ◽

Hai-Bo Wang ◽

Li Ma ◽

Xiao-Xin Ren ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cell Differentiation ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Differentiation ◽

Naïve T Cell ◽

Hiv 1 ◽

Naive T Cell

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Human Mesenchymal Cells Regulates Naive and Memory T Regulatory Cells.

Blood ◽

10.1182/blood.v108.11.1734.1734 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1734-1734

Author(s):

Mauro Di Ianni ◽

Beatrice Del Papa ◽

Lorenzo Moretti ◽

Paolo Sportoletti ◽

Elisabetta Bonifacio ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

Peripheral Blood ◽

Foxp3 Expression ◽

Mesenchymal Cells ◽

Regulatory Function ◽

Cell Phenotype ◽

Naïve T Cell ◽

Naive T Cell

Abstract CD4(+)CD25(+)FoxP3(+) T regulatory (T reg) cells constitute 1–2% of peripheral blood cells in adults and function prevalently as immunosuppressors. 70% of T reg are memory/effector cells with a CD45RO+ phenotype. The other 30% have a naive T cell phenotype (CD45RA+). Both sub-populations exert a regulatory function and when sorted and/or purified each inhibits a mixed lymphocyte culture. In the present study, we investigated the effects of human recombinant IL-7 (rIL-7), human mesenchymal cells (hMSC) and hMSC engineered with the IL-7 gene (hMSC/IL-7) on regulatory T cells expressing a memory (CD4/CD25/CD45RO) or naive (CD4/CD25/CD45RA) phenotype. T cells from healthy donors were enriched by immnuselection to provide populations of CD45RA+ cells (95 % ± 2.9) and CD45RO+ cells (97 % ± 0.25). Enriched naive and memory cells were cultured in presence rIL-7 (100 ng/ml), hMSC (ratio 5:1) or hMSC/IL-7 (ratio 5:1). After 7 days’ culture we examined the CD4/CD25+ cells within the naive and memory populations. In the naive T cell population the T reg starting fraction of 0.05 % ± 0.01 of CD4/CD25 positive cells, did not change in the presence of rIL-7 while it rose to 0.2 % ± 0.14 in presence of human MSC and more interestingly reached 1.67 % ± 0.6 in presence of IL-7 engineered human MSC. In the memory T cell population the T reg starting fraction of 0.3 % ± 0.05 of CD4/CD25 positive cells, did not change in presence of rIL-7 while it rose 1.5 % ± 0.9 in the presence of human MSC and more interestingly reached 11.55 % ± 7.5 in the presence of human IL-7 engineered-MSC. We analyzed CD127 expression within different groups. In the naive T reg starting fraction 3 % ± 1.2 expressed CD127 which was down-regulated to 0.96 % ± 0.5 in the presence of rIL-7, to 0.29 % ± 0.2 with human MSC and to 0.37 % ± 0.02 with human IL-7engineered-MSC. Memory T reg cells expressed CD127 in 15% ± 1.2 of the starting fraction which was down-regulated to 1.2 % ± 0.45 in the presence of rIL-7, to 1.32 % ± 0.34 with hMSC and to 4.01% ± 0.74 in presence of hMSC/IL-7. FoxP3 expression was measured by real time quantitative PCR in sort-purified subsets of peripheral blood, identified by staining with a combination of CD4, CD25, CD45RA or CD45RO. In naive T reg FoxP3 expression was increased 1.15 fold in the presence of hMSC and 2.7 fold in presence of hMSC/IL-7. In memory T reg FoxP3 expression was increased 1.14 fold in the presence of hMSC and 2.67 fold in presence of hMSC/IL-7. In conclusion naive T reg cells are IL-7 independent and up-regulated by human MSC. Engineering human MSC with the IL-7 gene enhanced up-regulation. Memory T reg cells are also IL-7 independent and are up-regulated by human MSC. Engineering human MSC with the IL-7 gene markedly increased up-regulation. The different regulatory systems may underlie different functions within the T reg sub-populations.

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Activation of Natural Killer T Cells by α-Galactosylceramide Rapidly Induces the Full Maturation of Dendritic Cells In Vivo and Thereby Acts as an Adjuvant for Combined CD4 and CD8 T Cell Immunity to a Coadministered Protein

Journal of Experimental Medicine ◽

10.1084/jem.20030324 ◽

2003 ◽

Vol 198 (2) ◽

pp. 267-279 ◽

Cited By ~ 519

Author(s):

Shin-ichiro Fujii ◽

Kanako Shimizu ◽

Caroline Smith ◽

Laura Bonifaz ◽

Ralph M. Steinman

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Natural Killer ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Cell Immunity ◽

Ifn Γ ◽

Natural Killer T

The maturation of dendritic cells (DCs) allows these antigen-presenting cells to initiate immunity. We pursued this concept in situ by studying the adjuvant action of α-galactosylceramide (αGalCer) in mice. A single i.v. injection of glycolipid induced the full maturation of splenic DCs, beginning within 4 h. Maturation was manifest by marked increases in costimulator and major histocompatibility complex class II expression, interferon (IFN)-γ production, and stimulation of the mixed leukocyte reaction. These changes were not induced directly by αGalCer but required natural killer T (NKT) cells acting independently of the MyD88 adaptor protein. To establish that DC maturation was responsible for the adjuvant role of αGalCer, mice were given αGalCer together with soluble or cell-associated ovalbumin antigen. Th1 type CD4+ and CD8+ T cell responses developed, and the mice became resistant to challenge with ovalbumin-expressing tumor. DCs from mice given ovalbumin plus adjuvant, but not the non-DCs, stimulated ovalbumin-specific proliferative responses and importantly, induced antigen-specific, IFN-γ producing, CD4+ and CD8+ T cells upon transfer into naive animals. In the latter instance, immune priming did not require further exposure to ovalbumin, αGalCer, NKT, or NK cells. Therefore a single dose of αGalCer i.v. rapidly stimulates the full maturation of DCs in situ, and this accounts for the induction of combined Th1 CD4+ and CD8+ T cell immunity to a coadministered protein.

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VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

Science ◽

10.1126/science.aay0524 ◽

2020 ◽

Vol 367 (6475) ◽

pp. eaay0524 ◽

Cited By ~ 22

Author(s):

Mohamed A. ElTanbouly ◽

Yanding Zhao ◽

Elizabeth Nowak ◽

Jiannan Li ◽

Evelien Schaafsma ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Subset ◽

Peripheral Tolerance ◽

Cell Immune Response ◽

Naive T Cells ◽

Naïve T Cells ◽

Naïve T Cell ◽

Naive T Cell

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

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Batf3-Dependent Dendritic Cells Promote Optimal CD8 T Cell Responses against Respiratory Poxvirus Infection

Journal of Virology ◽

10.1128/jvi.00495-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 9

Author(s):

Pritesh Desai ◽

Vikas Tahiliani ◽

Georges Abboud ◽

Jessica Stanfield ◽

Shahram Salek-Ardakani

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Vaccinia Virus ◽

Respiratory Infection ◽

Host Resistance ◽

T Cell Responses ◽

Cell Responses ◽

Ifn Γ ◽

The Impact

ABSTRACTRespiratory infection with vaccinia virus (VacV) elicits robust CD8+T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8+effector T cell responses remains poorly defined. We used Batf3−/−mice to investigate the impact of CD103+and CD8α+dendritic cell (DC) deficiency on anti-VacV CD8+T cell responses. We found that Batf3−/−mice were more susceptible to VacV infection, exhibiting profound weight loss, which correlated with impaired accumulation of gamma interferon (IFN-γ)-producing CD8+T cells in the lungs. This was largely due to defective priming since early in the response, antigen-specific CD8+T cells in the draining lymph nodes of Batf3−/−mice expressed significantly reduced levels of Ki67, CD25, and T-bet. These results underscore a specific role for Batf3-dependent DCs in regulating priming and expansion of effector CD8+T cells necessary for host resistance against acute respiratory VacV infection.IMPORTANCEDuring respiratory infection with vaccinia virus (VacV), a member ofPoxviridaefamily, CD8+T cells play important role in resolving the primary infection. Effector CD8+T cells clear the virus by accumulating in the infected lungs in large numbers and secreting molecules such as IFN-γ that kill virally infected cells. However, precise cell types that regulate the generation of effector CD8+T cells in the lungs are not well defined. Dendritic cells (DCs) are a heterogeneous population of immune cells that are recognized as key initiators and regulators of T-cell-mediated immunity. In this study, we reveal that a specific subset of DCs that are dependent on the transcription factor Batf3 for their development regulate the magnitude of CD8+T cell effector responses in the lungs, thereby providing protection during pulmonary VacV infection.

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