Hosts Lacking Fms-Like Tyrosine Kinase 3 Ligand Exhibit Marked Reductions in Transplant Vascular Sclerosis

Wang, Zhiliang; Taner, Timuçin; Morelli, Adrián E.; Thomson, Angus W.

doi:10.1097/01.tp.0000157120.43052.3a

Cited by 5 publications

(5 citation statements)

References 21 publications

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“…Our results, however, may help explain some observations in published studies. First, consistent with our observation that FLT3 is a repressor of IL-10 production, an increase in IL-10 levels was observed in FLT3-deficient mice with an allogeneic aorta graft (45). While this effect was attributed to dendritic cells, our results suggest an additional role for T cells.…”

Section: Discussionsupporting

confidence: 89%

RNA Interference Screen in Primary Human T Cells Reveals FLT3 as a Modulator of IL-10 Levels

Astier

Bériou

Eisenhaure

et al. 2009

The Journal of Immunology

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Functional studies of human primary immune cells have been hampered by the lack of tools to silence gene functions. Here we report the application of a lentiviral RNAi library in primary human T cells. Using a subgenomic shRNA library targeting ~1,000 signaling genes, we identified novel genes that control the levels of IL-10 produced. IL-10 is a potent anti-inflammatory cytokine secreted by several cell types, including Tr1 cells, a subset of Tregs that exert their suppressive activity through IL-10 secretion. FLT3, a known hematopoeitic growth factor, was found to be a negative regulator of IL-10 levels in activated T cells. This was based on several observations. First, FLT3 and its ligand, FL, were both induced by T cell activation. Second, silencing of FLT3 led to increased IL-10 levels while addition of FL suppressed IL-10 secretion and increased FLT3 surface levels. Third, engagement of CD46, a known inducer of Tr1 regulatory T cells, upregulated surface FLT3 and secreted FL, which then inhibited IL-10 production in T cells. Hence, FL and FLT3 form a novel regulatory feedback loop that limits IL-10 production in T cells. Our results identified Flt3 as a new regulator of T cell function and offer a strategy to genetically dissect specific pathways in T cells.

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Section: Discussionsupporting

confidence: 89%

RNA Interference Screen in Primary Human T Cells Reveals FLT3 as a Modulator of IL-10 Levels

Astier

Bériou

Eisenhaure

et al. 2009

The Journal of Immunology

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“…2 F ), thus demonstrating their in vivo suppressive function. Flt3L has been reported to have both pro- and anti-inflammatory effects in disease models (23–25). Thus, the varying impact of Flt3L on immune responses in vivo remains poorly understood, and the role of MDSC in these models has not been explored.…”

Section: Resultsmentioning

confidence: 99%

Cutting Edge: Flt3 Ligand Mediates STAT3-Independent Expansion but STAT3-Dependent Activation of Myeloid-Derived Suppressor Cells

Rosborough

Mathews

Matta

et al. 2014

The Journal of Immunology

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The Flt3-Flt3 ligand (Flt3L) pathway is critically involved in the differentiation and homeostasis of myeloid cells, including dendritic cells (DC); however, its role in the expansion and function of myeloid-derived suppressor cells (MDSC) has not been determined. Herein, we describe the ability of Flt3L to expand and activate murine MDSC capable of suppressing allograft rejection upon adoptive transfer. While Flt3L expands and augments the stimulatory capacity of myeloid DC, MDSC expanded by Flt3L have increased suppressive activity. Although STAT3 is considered the central transcription factor for MDSC expansion, inhibition and genetic ablation of STAT3 did not block, but augmented Flt3L-mediated MDSC expansion. MDSC suppressive function, preserved when STAT3 inhibition was removed, was reduced by genetic STAT3 deletion. Both STAT3 inhibition and deletion reduced Flt3L-mediated DC expansion, signifying that STAT3 had reciprocal effects on suppressive MDSC and immunostimulatory DC expansion. Together, these findings enhance understanding of the immunomodulatory properties of Flt3L.

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“…EBV-specific tetramer + (TMR + )-sorted CD8 + T cells were stimulated with PMA (5 ng/mL) + ionomycin (100 ng/mL) for an additional 24 h at 37 • C, 5% CO2, then exposed to Brefeldin A for the last 4 h of incubation. Aliquots of 10 5 cells/200 lL were then used to generate cytospins, as described (16).…”

Section: Intracellular Cytokine Analysis By Fluorescence Microscopymentioning

confidence: 99%

“…Intracellular cytokines produced in response to PMA + ionomycin were detected by indirect staining with: mouse anti-human IFNc mAb from BD-PharMingen, Cy2-conjugated donkey anti-mouse F(ab') 2 fragment from Jackson Immunoresearch (West Grove, PA), rat anti-human anti-IL-10 mAbs from BD-PharMingen and Alexa Fluor 647-conjugated goat anti-rat F(ab') 2 from Molecular Probes (Eugene, OR). Nuclei were counterstained with 4,6diamidino-2-phenylindole 2HCl (DAPI-Molecular Probes) (16). Microscopic examination was performed with an OLYMPUS microscope model BX40 and Microphoto OM system.…”

Section: Novel Anti-ebv Treg Pathway In Transplant Patientsmentioning

confidence: 99%

EBV-Specific CD8+ T Cell Reactivation in Transplant Patients Results in Expansion of CD8+ Type-1 Regulatory T Cells

Popescu¹,

Macedo²,

Abu‐Elmagd³

et al. 2007

American Journal of Transplantation

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Posttransplantation lymphoproliferative disorders (PTLD) are life-threatening complications of solid organ transplantation, triggered by EBV infection in chronically immunosuppressed (IS) patients. Our goal is to establish DC-based protocols for adoptive immunotherapy of refractory PTLD, while understanding how the immunosuppressive drug environment may subvert DC-EBV-specific T cell interactions. Type-1 CD8 + T cells are critical for efficient immune surveillance and control of EBV infection, whereas type-2 or Treg/type-3 responses may provide an environment conductive to disease progression. We have recently reported that chronic IS inhibits DC function in transplant patients. Here, we have analyzed the comparative ability of mature, type-1 polarized DCs (i.e. DC1) generated from quiescent transplant patients or healthy controls, to boost type-1 EBV-specific CD8 + T cells in vitro. Our results show that unlike healthy controls, where DC1 loaded with MHC class I EBV peptides preferentially reactivate specific type-1 CD8 + T cells, DC1 generated from transplant patients reactivate EBV-specific CD8 + T cells that produce both IFN-c and IL-10, up-regulate FOXP3 mRNA, and suppress noncognate CD4 + T-cell proliferation via cell-cell contact. These data support a novel regulatory pathway for anti-EBV T-cell-mediated responses in IS transplant patients, with implications for the design of adoptive immunotherapies in this setting.

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Hosts Lacking Fms-Like Tyrosine Kinase 3 Ligand Exhibit Marked Reductions in Transplant Vascular Sclerosis

Abstract: Permanent deficiency of host DC subsets resulting from targeted gene disruption markedly inhibits the development of transplant vascular sclerosis, associated with striking reductions in both anti-donor T-cell reactivity and immunoglobulin-G alloantibody production.

Cited by 5 publications

References 21 publications

RNA Interference Screen in Primary Human T Cells Reveals FLT3 as a Modulator of IL-10 Levels

RNA Interference Screen in Primary Human T Cells Reveals FLT3 as a Modulator of IL-10 Levels

Cutting Edge: Flt3 Ligand Mediates STAT3-Independent Expansion but STAT3-Dependent Activation of Myeloid-Derived Suppressor Cells

EBV-Specific CD8+ T Cell Reactivation in Transplant Patients Results in Expansion of CD8+ Type-1 Regulatory T Cells

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