Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3+ Regulatory T Cell Development and Function: Implications for Osteoclastogenesis
Sebastian DohnkeStephanie MoehserAlexey SurnovThomas KurthRolf JessbergerKarsten KretschmerAnnette I. Garbe
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In T cells, processes such as migration and immunological synapse formation are accompanied by the dynamic reorganization of the actin cytoskeleton, which has been suggested to be mediated by regulators of RhoGTPases and by F-actin bundlers. SWAP-70 controls F-actin dynamics in various immune cells, but its role in T cell development and function has remained incompletely understood. CD4 + regulatory T (Treg) cells expressing the transcription factor Foxp3 employ diverse mechanisms to suppress innate and adaptive immunity, which is critical for maintaining immune homeostasis and self-tolerance. Here, we propose Swap-70 as a novel member of the Foxp3-dependent canonical Treg cell signature. We show that Swap-70 -/- mice have increased numbers of Foxp3 + Treg cells with an effector/memory-like phenotype that exhibit impaired suppressor function in vitro , but maintain overall immune homeostasis in vivo . Upon formation of an immunological synapse with antigen presenting cells in vitro , cytosolic SWAP-70 protein is selectively recruited to the interface in Treg cells. In this context, Swap-70 -/- Treg cells fail to downregulate CD80/CD86 on osteoclast precursor cells by trans-endocytosis and to efficiently suppress osteoclastogenesis and osteoclast function. These data provide first evidence for a crucial role of SWAP-70 in Treg cell biology and further highlight the important non-immune function of Foxp3 + Treg cells in bone homeostasis mediated through direct SWAP-70-dependent mechanisms.Keywords:
Immunological synapse
T cell activation requires formation of a specialized cell-cell junction, the immunological synapse (Paul and Seder, 1994). The authors have hypothesized that segregation will be an important process for T cell activation (Shaw and Dustin, 1997). To test these hypotheses and to explore the engineering principles behind these events the authors have developed a model system in which formation of an immunological synapse is quantitatively visualized in real time. Molecular segregation of engaged MHC-peptide and ICAM-1 complexes was strongly correlated with T cell proliferation. These data support the hypothesis that molecular segregation is important for T cell signaling.
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A bstract : T cell activation is based on interactions of T cell antigen receptors with MHC‐peptide complexes in a specialized cell‐cell junction between the T cell and antigen‐presenting cell—the immunological synapse. The immunological synapse coordinates naïve T cell activation and migration by stopping T cell migration with antigen‐presenting cells bearing appropriate major histocompatibility complex (MHC) peptide complexes. At the same time, the immunological synapse allows full T cell activation through sustained signaling over a period of several hours. The immunological synapse supports activation in the absence of continued T cell migration, which is required for T cell activation through serial encounters. Src and Syk family kinases are activated early in immunological synapse formation, but this signaling process returns to the basal level after 30 min; at the same time, the interactions between T cell receptors (TCRs) and MHC peptides are stabilized within the immunological synapse. The molecular pattern of the mature synapse in helper T cells is a self‐stabilized structure that is correlated with cytokine production and proliferation. I propose that this molecular pattern and its specific biochemical constituents are necessary to amplify signals from the partially desensitized TCR.
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The signaling pathways that lead to the localization of cellular protein to the area of interaction between T cell and antigen-presenting cell and the mechanism by which these molecules are further sorted to the peripheral supramolecular activation cluster or central supramolecular activation cluster regions of the immunologic synapse are poorly understood. In this study, we investigated the functional involvement of CD28 costimulation in the T cell receptor (TCR)-mediated immunologic synapse formation with respect to protein kinase C (PKC)θ localization. We showed that CD3 crosslinking alone was sufficient to induce PKCθ capping in naïve CD4 + T cells. Studies with pharmacologic inhibitors and knockout mice showed that the TCR-derived signaling that drives PKCθ membrane translocation requires the Src family kinase, Lck, but not Fyn. In addition, a time course study of the persistence of T cell molecules to the immunologic synapse indicated that PKCθ, unlike TCR, persisted in the synapse for at least 4 h, a time that is sufficient for commitment of a T cell to cell division. Finally, by using TCR-transgenic T cells from either wild-type or CD28-deficient mice, we showed that CD28 expression was required for the formation of the mature immunologic synapse, because antigen stimulation of CD28 − T cells led to a diffuse pattern of localization of PKCθ and lymphocyte function-associated antigen-1 in the immunologic synapse, in contrast to the central supramolecular activation cluster localization of PKCθ in CD28 + T cells.
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T cell activation requires formation of a specialized cell-cell junction, the immunological synapse (Paul and Seder, 1994). The authors have hypothesized that segregation will be an important process for T cell activation (Shaw and Dustin, 1997). To test these hypotheses and to explore the engineering principles behind these events the authors have developed a model system in which formation of an immunological synapse is quantitatively visualized in real time. Molecular segregation of engaged MHC-peptide and ICAM-1 complexes was strongly correlated with T cell proliferation. These data support the hypothesis that molecular segregation is important for T cell signaling.
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Abstract Aging is associated with reduced IL-2 production and T cell proliferation. Vitamin E supplementation, in aged animals and humans, increases cell division and IL-2 production by naive T cells. The immune synapse forms at the site of contact between a T cell and an APC and participates in T cell activation. We evaluated whether vitamin E affects the redistribution of signaling proteins to the immune synapse. Purified CD4+ T cells, from the spleens of young and old mice, were treated with vitamin E before stimulation with a surrogate APC expressing anti-CD3. Using confocal fluorescent microscopy, we observed that CD4+ T cells from old mice were significantly less likely to recruit signaling proteins to the immune synapse than cells from young mice. Vitamin E increased the percentage of old CD4+ T cells capable of forming an effective immune synapse. Similar results were found following in vivo supplementation with vitamin E. When compared with memory cells, naive T cells from aged mice were more defective in immune synapse formation and were more responsive to vitamin E supplementation. These data show, for the first time, that vitamin E significantly improves age-related early T cell signaling events in naive CD4+ T cells.
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