Cutting Edge: Granulocyte-Macrophage Colony-Stimulating Factor Is the Major CD8+ T Cell-Derived Licensing Factor for Dendritic Cell Activation

Miao, Lin; Isa, Siti Aminah Bte Mohammad; Wang, Shuai; Cher, Boon Piang; Nih, Fam Wee; Kotaka, Masayo; Ruedl, Christiane

doi:10.4049/jimmunol.0903873

Cited by 70 publications

(63 citation statements)

References 20 publications

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“…Upregulation of both molecules was further increased in the presence of GM-CSF (Fig. 6A), corroborating the previous studies [19,28]. However, this upregulation of activation molecules in GM-CSF licensed DCs can only explain the augmented ability of splenic DCs to support T-cell proliferation, since thymic DCs did not require licensing to induce efficient T-cell proliferation, and both freshly isolated and cultured thymic and splenic CD8 1 DCs showed no major difference in the expression of CD80 and CD86 (Figs.…”

Section: Thymic Cd103supporting

confidence: 92%

“…This discrepancy may be due to the fact that in the previous studies, ex vivo cross-priming assays have been performed in the presence of GM-CSF and/or DCs have been isolated from Flt3 ligand-treated mice. Accordingly, it has been recently demonstrated that, similar to CD40 ligand, GM-CSF is a licensing factor that activates DCs [19]. To explore this possibility, we performed T-cell proliferation assays in the presence of GM-CSF, and found that in this situation splenic CD8 1 DCs were indeed able to efficiently cross-prime and induce proliferation of 8078% of OT-I cells, which is comparable to the efficiency of the thymic CD8 1 DCs (Fig.…”

mentioning

confidence: 71%

“…6A and [19,28]). While the upregulation of costimulatory molecules by GM-CSF may contribute to enhance the cross-priming capacity of splenic CD8 1 DCs, it cannot explain the superior cross-priming capacity of thymic CD8 1 DCs in the absence of licensing, since freshly isolated and cultured thymic DCs did not present major differences in overall DC maturation/activation when compared with splenic DCs (Figs.…”

Section: Licensing the Defect Of Splenic Cd8mentioning

confidence: 99%

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Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

et al. 2011

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Cross-presentation is an important mechanism to elicit both immune defenses and tolerance. Although only a few DC subsets possess the machinery required for crosspresentation, little is known about differences in cross-presenting capabilities of DCs belonging to the same subpopulation but localized in different lymphoid organs. In this study, we demonstrate that steady-state thymic CD81 DCs can efficiently cross-prime naïve CD8 1 T cells in the absence of costimulation. Surprisingly, cross-priming by splenic CD8 1 DCs was dependent on licensing factors such as GM-CSF. In the absence of GM-CSF,antigen-MHC-class-I complexes were detected on thymic but not on splenic CD8 1 DCs, indicating that the cross-presentation capacity of the thymic subpopulation was higher. The observed cross-priming differences between thymic and splenic CD8 1 DCs did not correlate with differential antigen capture or costimulatory molecules found on the surface of DCs. Moreover, we did not detect overall impairment of antigen presentation, as peptide-loaded splenic CD8 1 DCs were able to induce CD8 1 T-cell proliferation. The observation that thymic CD8 1 DCs are more efficient than splenic CD8 1 DCs in T-cell cross-priming in the absence of licensing factors indicates that the requirements for efficient antigen presentation differ between these cells.

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Section: Thymic Cd103supporting

confidence: 92%

mentioning

confidence: 71%

Section: Licensing the Defect Of Splenic Cd8mentioning

confidence: 99%

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Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

et al. 2011

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“…GM-CSF can be produced by macrophages but, interestingly, apparently not by DC (49). In vivo, ongoing DC recruitment and differentiation in the setting of tissue inflammation may be highly dependent on other cell types (28) and the supply of critical cytokines such as GM-CSF (51,52 findings of previous reports (36,37) that show normal cDC development and function in Nfkb1 2/2 mice, with a marginal reduction in numbers being the main difference to WT mice. Importantly, we found MoDC in the directly involved joint tissue of WT mice with inflammatory arthritis, and MoDC were identified as a likely target for CD4 T cell-derived GM-CSF.…”

Section: Discussionmentioning

confidence: 79%

“…T cells appear to lack GM-CSF receptors; thus, this effect was most likely via enhancement of IL-6 and IL-23 production from APC. Although it was previously thought that GM-CSF 2/2 mice had normal DC (50), GM-CSF was recently found to be required for the accumulation of Langerin + CD103 + DC (51), and GM-CSF production by CD8 + T cells, in combination with microbial stimuli, was postulated as a "licensing factor" for DC (52). GM-CSF can be produced by macrophages but, interestingly, apparently not by DC (49).…”

Section: Discussionmentioning

confidence: 99%

Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-κB1–Dependent GM-CSF Production in CD4 T Cells

Campbell

Nieuwenhuijze

Ségura

et al. 2011

The Journal of Immunology

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Rel/NF-κB transcription factors regulate inflammatory and immune responses. Despite possible subunit redundancy, NF-κB1–deficient (Nfkb1−/−) mice were profoundly protected from sterile CD4 T cell-dependent acute inflammatory arthritis and peritonitis. We evaluated CD4 T cell function in Nfkb1−/− mice and found increased apoptosis and selectively reduced GM-CSF production. Apoptosis was blocked by expression of a Bcl-2 transgene without restoring a disease response. In contrast with wild-type cells, transfer of Nfkb1−/− or GM-CSF–deficient CD4 T cells into RAG-1–deficient (Rag1−/−) mice failed to support arthritis induction. Injection of GM-CSF into Nfkb1−/− mice fully restored the disease response, suggesting that T cells are an important source of GM-CSF during acute inflammation. In Ag-induced peritonitis, NF-κB1–dependent GM-CSF production in CD4 T cells was required for disease and for generation of inflammatory monocyte-derived dendritic cells (MoDC), but not conventional dendritic cells. MoDC were identified in inflamed synovium and draining lymph nodes during arthritis. These MoDC produced high levels of MCP-1, a potent chemoattractant for monocytes. This study revealed two important findings: NF-κB1 serves a critical role in the production of GM-CSF by activated CD4 T cells during inflammatory responses, and GM-CSF derived from these cells drives the generation of MoDC during inflammatory disease.

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From crucial to negligible: Functional CD8⁺T‐cell responses and their dependence on CD4⁺T‐cell help

2012

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CD8 + T cells play an important role in controlling pathogenic infections and are therefore key players in the immune response. It has been shown that among other factors CD4 + T cells can shape the magnitude as well as the quality of primary and/or secondary CD8 + T-cell responses. However, due to the complexity and the differences among diverse immunization or infection models, the overall requirement, the time points, as well as the specific mechanism(s) of CD4 + T-cell help may differ substantially. Here, we summarize current knowledge about the differential requirement of CD4 + T-cell help in promoting primary CD8 + T-cell responses as well as establishing functional memory CD8 + T cells in various experimental settings. Keywords: CD8 + T cells r Differentiation r Memory r T-cell help CD8 + T-cell responsesA number of different parameters influence, by virtue of their strength and composition, CD8 + T-cell activation; they subsequently also shape the size and the phenotypical and functional properties of the resultant memory CD8 + T-cell pool. These parameters include antigen-specific T-cell precursor frequencies [1], the strength of the T-cell receptor interaction with peptide-MHC complexes, and the signals provided by co-stimulatory receptors, as well as innate immune system derived inflammatory cytokines [2,3]. Among the factors that modulate the activation of dendritic cells (DCs), the cells that are the main inducers of CD8 + T-cell responses, is the help provided by CD4 + T cells. CD4 + T-cell engagement of DCs promotes the upregulation of certain costimulatory molecules (such as CD80 and CD86) on, as well as the release of pro-inflammatory cytokines such as IL-12 by, DCs. Thus, in many defined experimental settings, T helper cells have been implicated in the expansion and survival of CD8 + T cells during the primary response, and have a key role in establishing long-lived, functionally robust memory CD8 + T-cell responses [4][5][6][7]. The concept of T-cell help for CD8 + T-cell responses was Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch further supported by the finding that chemokines secreted by activated CD4 + T helper cells can play a key role in the recruitment of naïve antigen-specific CD8 + T cells to antigen-bearing antigen presenting cells (APCs) in secondary lymphoid organs [8] or to sites of infection [9]. Moreover, in some experimental settings CD4 + T cells were proposed to directly interact with CD8 + T cells, thereby promoting their activation and expansion [10]. Hence, the overall contribution, as well as the mechanism, of helper CD4 + T cells in the initiation of primary and secondary CD8 + T-cell responses is more complex than initially believed and appears to strongly depend on the specific biology of the immunization/infection system.

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Cutting Edge: Granulocyte-Macrophage Colony-Stimulating Factor Is the Major CD8+ T Cell-Derived Licensing Factor for Dendritic Cell Activation

Abstract: Material

Cited by 70 publications

References 20 publications

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-κB1–Dependent GM-CSF Production in CD4 T Cells

From crucial to negligible: Functional CD8⁺T‐cell responses and their dependence on CD4⁺T‐cell help

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Cutting Edge: Granulocyte-Macrophage Colony-Stimulating Factor Is the Major CD8+ T Cell-Derived Licensing Factor for Dendritic Cell Activation

Abstract: Material

Cited by 70 publications

References 20 publications

Thymic but not splenic CD8+ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Thymic but not splenic CD8+ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-κB1–Dependent GM-CSF Production in CD4 T Cells

From crucial to negligible: Functional CD8+T‐cell responses and their dependence on CD4+T‐cell help

Contact Info

Product

Resources

About

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

From crucial to negligible: Functional CD8⁺T‐cell responses and their dependence on CD4⁺T‐cell help