Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells

Mahnke, Karsten; Qian, Yingjie; Knop, J.; Enk, Alexander H.

doi:10.1182/blood-2002-10-3229

Cited by 362 publications

(284 citation statements)

References 35 publications

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“…No evidence of immune deviation to Th2 cytokine production was observed. Previously, differentiation of Foxp3 1 Treg from naïve CD4 1 T cells has been shown when antigen is targeted to DC [28]. Although more OT-II T cells in 11c.OVA recipients expressed Foxp3 this was, overall, only a very small proportion of residual OT-II cells 21 days after transfer indicating conversion to Treg made no substantial contribution to tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

et al. 2010

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CD4 1 T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T-cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T-cell responses. Here, we demonstrate that CD4 1 memory T-cell responses can be terminated when cognate antigen is transgenically expressed in steady-state DC. Transfer of in-vitrogenerated CD4 1 memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4 1 T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T-cell-mediated autoimmune and inflammatory diseases.Key words: CD4 1 T cells . DC . Tolerance See accompanying Commentary by Kurts IntroductionNegative selection and peripheral tolerance mechanisms jointly serve to limit the development of autoaggressive self-reactive T-cell responses. However, in autoimmune-prone individuals these control mechanisms can fail and autoimmune disease ensues. As autoimmune diseases progress, intra-and intermolecular determinant spreading occurs [1] and populations of effector and memory T cells become established. Therefore, unlike strategies directed at preventing the development of autoimmune disease, where induction of tolerance in naïve T cells may be all that is required, therapies aimed at terminating ongoing autoimmune disease must be capable of inactivating established populations of memory or activated effector T cells.Although naïve T cells are highly dependent on the presence or absence of costimulatory signals to determine the outcome of activation, costimulation appears to play little role in controlling the responses of memory and effector T cells [2,3] and these cells are considered costimulation independent. Because of this, in contrast to naïve T cells which are readily deleted or inactivated in the absence of costimulation memory T cells are widely regarded as potentially resistant to tolerance induction. If this were indeed the case, then effector and memory T cells represent a significant hurdle to therapeutic strategies aimed at treating autoimmune diseases. However, we have recently shown that memory and effector CD8 1 T cells are susceptible to tolerance induction when cognate antigen is expressed in DC and other APC types [4]. 2016The relative roles of CD4 1 and CD8 1 T cells in disease progression differ depending on the autoimmune disease bu...

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Section: Discussionmentioning

confidence: 99%

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

et al. 2010

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“…Additionally, as a result of the difficulties associated with ex vivo generated DC vaccines, the notion of in situ targeting of DCs and thus use of the efficient migratory properties of DCs in vivo is gaining popularity (57). Of course, proper DC maturation and activation is mandatory to induce immunity in such a case, because the absence of inflammation will induce Ag tolerance (58). Among the attempts to target DCs in situ and at the same time provide appropriate maturation and activation stimuli, the use of a synthetic CpG oligonucleotide, which is known to trigger TLR 9, to immunize melanoma patients with a Melan-A peptide in a clinical trial yielded particularly successful results (59).…”

Section: Discussionmentioning

confidence: 99%

All-trans Retinoic Acid Enhances Murine Dendritic Cell Migration to Draining Lymph Nodes via the Balance of Matrix Metalloproteinases and Their Inhibitors

Darmanin

Chen²,

Zhao

et al. 2007

The Journal of Immunology

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Cancers escape immune surveillance through the manipulation of the host’s immune system. Sequestration of dendritic cells (DCs) within tumor tissues and the subsequent inhibition of their migration is one of the several mechanisms by which tumors induce immunosuppression. In view of recent findings depicting the improvement of tumor immune responses in cancer patients following all-trans retinoic acid (ATRA) treatment, we sought to identify the effects of ATRA on DC mobility in the context of tumor immunotherapy. Our results demonstrate that ATRA, added to differentiating murine bone marrow progenitor cells, enhances the invasive capacity of the resulting DCs. Immature DCs injected intratumorally in mice show increased accumulation in draining lymph nodes, but not in nondraining lymph nodes and spleens, when differentiated in the presence of ATRA. The in vitro migration of mature DCs through the basement membrane matrix toward the lymphoid chemokines CCL19 and CCL21 is enhanced in these cells, albeit not in the presence of a matrix metalloproteinase (MMP) inhibitor. An increase in MMP production with a simultaneous decrease in the production of their inhibitors (tissue inhibitors of matrix metalloproteinase or TIMPs) is provoked by ATRA. This affects the MMP/TIMP balance in DCs, in particular that of MMP-9 and TIMP-1, favoring protease activity and thus allowing for enhanced DC mobilization. In conclusion, this study demonstrates that ATRA is capable of improving DC trafficking in a tumor milieu and, in view of the encouraging results obtained in the clinic, further supports the notion that ATRA might be a valuable chemical adjuvant to current immunotherapeutic strategies for cancer.

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“…TGF-␤ maintains the suppressive functions of Tregs (12). DCs also contribute to controlling Treg cell functions by supporting the expansion of functional Tregs in an Ag-specific manner (13), and immature DCs selectively induce Tregs (14). TLR signaling in DCs blocks Treg-mediated suppression by affecting effector T cells (15) and reverses suppression of Tregs (16).…”

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confidence: 99%

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

Hisaeda

Tetsutani

Imai

et al. 2008

The Journal of Immunology

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Malaria is still a life-threatening infectious disease that continues to produce 2 million deaths annually. Malaria parasites have acquired immune escape mechanisms and prevent the development of sterile immunity. Regulatory T cells (Tregs) have been reported to contribute to immune evasion during malaria in mice and humans, suggesting that activating Tregs is one of the mechanisms by which malaria parasites subvert host immune systems. However, little is known about how these parasites activate Tregs. We herein show that TLR9 signaling to dendritic cells (DCs) is crucial for activation of Tregs. Infection of mice with the rodent malaria parasite Plasmodium yoelii activates Tregs, leading to enhancement of their suppressive function. In vitro activation of Tregs requires the interaction of DCs with parasites in a TLR9-dependent manner. Furthermore, TLR9−/− mice are partially resistant to lethal infection, and this is associated with impaired activation of Tregs and subsequent development of effector T cells. Thus, malaria parasites require TLR9 to activate Tregs for immune escape.

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Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells

Cited by 362 publications

References 35 publications

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

All-trans Retinoic Acid Enhances Murine Dendritic Cell Migration to Draining Lymph Nodes via the Balance of Matrix Metalloproteinases and Their Inhibitors

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

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Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells

Cited by 362 publications

References 35 publications

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

All-trans Retinoic Acid Enhances Murine Dendritic Cell Migration to Draining Lymph Nodes via the Balance of Matrix Metalloproteinases and Their Inhibitors

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

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Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses