Activation through CD40 ligation induces functional Fas ligand expression by Langerhans cells

Shibaki, Akihiko; Katz, Stephen I.

doi:10.1002/1521-4141(2001010)31:10<3006::aid-immu3006>3.0.co;2-l

Cited by 31 publications

(20 citation statements)

References 50 publications

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“…In these earlier studies, many and diverse mechanisms of action were suggested, including immune-specific tolerance through the induction of T-regulatory cells, IL-10 secretion, and IL-2 inhibition 3,9,12,37 ; nonspecific inhibition through the NO system 10,38-40 ; inhibition via indoleamine 2,3-dioxygenase 37,41 ; and apoptosis through death receptors including Fas, TRAIL, and TNF. [13][14][15]17,39,42,43 Likewise, our results suggest that BM-derived DCs obtained after culturing of whole BM with either GM-CSF (supplemental Figure 4) or FLT3 ligand 44 (supplemental Figure 5) do not exhibit detectable levels of perforin or appreciable killing of cognate 2C CD8 T cells. Therefore, our results suggest that the perforin ϩ imDCs grown in our study from purified HSCs represent a novel subpopulation found in a small percentage in the spleen under steady state, which nevertheless can expand in the spleen after GM-CSF administration in vivo.…”

Section: Discussionmentioning

confidence: 73%

Deletion of cognate CD8 T cells by immature dendritic cells: a novel role for perforin, granzyme A, TREM-1, and TLR7

Zangi

Klionsky

Yarimi

et al. 2012

Blood

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Immature dendritic cells (imDCs) can have a tolerizing effect under normal conditions or after transplantation. However, because of the significant heterogeneity of this cell population, it is extremely difficult to study the mechanisms that mediate the tolerance induced or to harness the application of imDCs for clinical use. In the present study, we describe the generation of a highly defined population of imDCs from hematopoietic progenitors and the direct visualization of the fate of TCR-transgenic alloreactive CD4 ؉ and CD8 ؉ T cells after encountering cognate or noncognate imDCs. Whereas CD4 ؉ T cells were deleted via an MHC-independent mechanism through the NO system, CD8 ؉ T-cell deletion was found to occur through a unique MHCdependent, perforin-based killing mechanism involving activation of TLR7 and signaling through Triggering Receptor-1 Expressed on Myeloid cells (TREM-1). This novel subpopulation of perforinexpressing imDCs was also detected in various lymphoid tissues in normal animals and its frequency was markedly enhanced after GM-CSF administration. IntroductionCentral and peripheral tolerance mechanisms are critical for the establishment of a robust immune response that can distinguish between self-and nonself-antigens. Although the majority of self-specific T cells are deleted by negative selection in the thymus, some self-reactive T cells are spared and can reach peripheral organs. 1,2 A wealth of evidence indicates that dendritic cells (DCs) have tolerogenic capacity in their immature state (imDCs). [3][4][5][6][7][8] In the context of allogeneic organ transplantation, infusion of imDCs expressing the relevant MHC-peptide complex can prolong allograft survival in vivo. 7,[9][10][11][12] At the same time, imDCs can become immunogenic on maturation/activation in the presence of a danger signal such as lipopolysaccharide (LPS). However, this simplistic paradigm was recently challenged by the demonstration that fully mature DCs can also induce tolerance under the appropriate conditions, [13][14][15][16][17] suggesting a more complex decision-making process in which the net effect of Ag dose, DC lineage, DC maturation and activation state, and the cytokine milieu at the site of inflammation determine whether immunogenic or tolerogenic DC activity will prevail. 18 The tolerogenic potential of immature or mature DCs can be further extended to the resolution of inflammatory responses to pathogens. 19 Lymphoid organs, including spleen, bone marrow (BM), lymph nodes, and thymus, contain multiple DC subpopulations largely defined by their distinct anatomical location and phenotypes. 20,21 For example, the mouse spleen harbors plasmacytoid DCs (pDCs) and the CD8 ϩ and CD8 Ϫ subsets of classic DCs (cDCs). 20 Apart from the major steady-state dichotomy of differentiation into pDCs versus cDCs, an additional distinct monocyte-derived DC subset with phenotypic characteristics of cDCs is recruited to sites of inflammation. 22 The phenotypic heterogeneity of DCs and growing data on their distinct origins p...

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Section: Discussionmentioning

confidence: 73%

Deletion of cognate CD8 T cells by immature dendritic cells: a novel role for perforin, granzyme A, TREM-1, and TLR7

Zangi

Klionsky

Yarimi

et al. 2012

Blood

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“…Interestingly, FasL-expressing regulatory diffDC did not express CD8a (data not shown). It was reported that Langerhans cells could express FasL and induce apoptosis of Jurkat cells after activation through CD40 ligation (43). Bone marrow DC grown in GM-CSF and IL-4 could express FasL and also induce Jurkat T cell apoptosis in a Fas-dependent pathway in vitro (39).…”

Section: Ifn-g From Activated Cd4 T Cells Induces No Production By Rementioning

confidence: 99%

Splenic Stroma-Educated Regulatory Dendritic Cells Induce Apoptosis of Activated CD4 T Cells via Fas Ligand-Enhanced IFN-γ and Nitric Oxide

Guo

et al. 2012

The Journal of Immunology

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Stromal microenvironments of bone marrow, lymph nodes, and spleen have been shown to be able to regulate immune cell differentiation and function. Our previous studies demonstrate that splenic stroma could drive mature dendritic cells (DC) to further proliferate and differentiate into regulatory DC subset that could inhibit T cell response via NO. However, how splenic stroma-educated regulatory DC release NO and whether other molecules are involved in the suppression of T cell response remain unclear. In this study, we show that splenic stroma educates regulatory DC to express high level of Fas ligand (FasL) by TGF-β via ERK activation. The findings, that inhibition of CD4 T cell proliferation by regulatory DC required cell-to-cell contact and FasL deficiency impaired inhibitory effect of regulatory DC, indicate that regulatory DC inhibit CD4 T cell proliferation via FasL. Then, regulatory DC have been found to be able to induce apoptosis of activated CD4 T cells via FasL in caspase 8- and caspase 3-dependent manner. Interestingly, FasL on regulatory DC enhanced IFN-γ production from activated CD4 T cells, and in turn T cell-derived IFN-γ induced NO production from regulatory DC, working jointly to induce apoptosis of activated CD4 T cells. Blockade of IFN-γ and NO could reduce the apoptosis induction. Therefore, our results demonstrated that splenic stroma-educated regulatory DC induced T cell apoptosis via FasL-enhanced T cell IFN-γ and DC NO production, thus outlining a new way for negative regulation of T cell responses and maintenance of immune homeostasis by regulatory DC and splenic stromal microenvironment.

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“…For instance, in mice, epidermal Langerhans cells are known to upregulate their cell-surface expression of FasL after activation with CD40 ligand, resulting in their ability to kill Jurkat cells via apoptosis. 5 We were unable to identify any published reports of tumor killing induced by conventional myeloid DC (mDC;…”

Section: Subsets Of Natural and Induced Kdcmentioning

confidence: 99%

Killer dendritic cells: mechanisms of action and therapeutic implications for cancer

Wesa

Storkus

2007

Cell Death Differ

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Dendritic cells (DC) are essential for the development and regulation of adaptive host immune responses against tumors. DC are heterogeneous and comprised of diverse cellular subsets. They are best known for mediating a crucial role in the initiation of acquired immunity by serving as professional antigen presenting cells (APC) that take up antigens in their local microenvironment, which are then processed and presented to naïve T cells in the context of major histocompatibility complex (MHC) class I and II molecules. In addition to these functions, DC can modulate the types of T cell responses they generate, and can also influence the responses of innate effectors, such as NK cells. There is also now evidence that they may mediate a more primordial role as innate, effector cells that are tumoricidal. 'Killer' DC (KDC) may represent a true 'multi-tasking' cell type that can sequentially act as a 'hunter-gatherer' of antigens; as well as, an instructor, then enforcer/regulator, of antigenspecific anti-tumor T-cell responses in vivo. In this review, we will critically examine the published record regarding KDC, their mechanism(s) of action, and then consider the potential integration of KDC into novel immunotherapies for patients with cancer.

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Activation through CD40 ligation induces functional Fas ligand expression by Langerhans cells

Cited by 31 publications

References 50 publications

Deletion of cognate CD8 T cells by immature dendritic cells: a novel role for perforin, granzyme A, TREM-1, and TLR7

Deletion of cognate CD8 T cells by immature dendritic cells: a novel role for perforin, granzyme A, TREM-1, and TLR7

Splenic Stroma-Educated Regulatory Dendritic Cells Induce Apoptosis of Activated CD4 T Cells via Fas Ligand-Enhanced IFN-γ and Nitric Oxide

Killer dendritic cells: mechanisms of action and therapeutic implications for cancer

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