Immunometabolism of regulatory T cells Newton, Ryan; Priyadharshini, Bhavana; Turka, Laurence A
Nature immunology,
06/2016, Letnik:
17, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate ...whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells.
PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here, we show that PTEN homodimerizes and, in this active conformation, exerts lipid phosphatase activity ...on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants heterodimerize with wild-type PTEN and constrain its phosphatase activity in a dominant-negative manner. To study the consequences of homo- and heterodimerization of wild-type and mutant PTEN in vivo, we generated Pten knockin mice harboring two cancer-associated PTEN mutations (PtenC124S and PtenG129E). Heterozygous PtenC124S/+ and PtenG129E/+ cells and tissues exhibit increased sensitivity to PI3-K/Akt activation compared to wild-type and Pten+/− counterparts, whereas this difference is no longer apparent between PtenC124S/− and Pten−/− cells. Notably, Pten KI mice are more tumor prone and display features reminiscent of complete Pten loss. Our findings reveal that PTEN loss and PTEN mutations are not synonymous and define a working model for the function and regulation of PTEN.
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•PTEN exists in an active, unphosphorylated dimeric conformation•PTEN missense mutations exert dominant-negative effects over the wild-type protein•Pten mutations elicit Akt hyperactivation and augmented tumorigenesis in the mouse•Mutant PTEN associates with increased AKT phosphorylation in human cancer
PTEN functions as a dimer, and cancer-associated PTEN mutants can act in a dominant-negative manner by heterodimerizing with and inhibiting the wild-type protein, revealing a tumorigenic and signaling mechanism for this well-known tumor suppressor.
Background Immunotherapy inhibits basophil histamine release, but the assay is cumbersome, and no one has studied the effects of immunotherapy withdrawal. Objective Intracellular fluorochrome-labeled ...diamine oxidase (DAO) was used as a novel functional readout of basophil histamine release after immunotherapy. Results were compared with conventional basophil surface expression of activation markers. Methods Subcutaneous immunotherapy (SCIT)–treated patients (n = 14), sublingual immunotherapy (SLIT)–treated patients (n = 12), participants who completed 3 years of treatment with grass pollen sublingual immunotherapy (the SLIT-TOL group; n = 6), patients with untreated seasonal allergic rhinitis (SAR; n = 24), and nonatopic control subjects (n = 12) were studied. Intracellularly labeled DAO+ and surface expression of CD203cbright , CD63+ , and CD107a+ on chemoattractant receptor-homologous molecule expressed on TH 2 lymphocytes (CRTh2)–positive basophils were measured by means of flow cytometry. Serum IgG4 levels and serum inhibitory activity for IgE-allergen complex binding to B cells (IgE-FAB) and basophil histamine release were also determined. Results Proportions of allergen-stimulated DAO+ CRTh2+ basophils were higher in participants in the SCIT, SLIT, and SLIT-TOL groups (all P < .0001) compared with those in patients in the SAR group. Similarly, there were lower proportions of CRTh2+ basophils expressing surface CD203cbright (all P < .001), CD63 (all P < .001), and CD107a (all P < .01). Rhinitis symptoms were lower in the SCIT, SLIT, and SLIT-TOL groups ( P < .001) compared with those in the SAR group. Serum inhibitory activity for IgE-FAB and basophil histamine release were also significantly greater in all immunotherapy groups ( P < .05) compared with the SAR group. Conclusion These results support long-term clinical and immunologic tolerance during and after grass pollen immunotherapy. Intracellularly labeled DAO expression by basophils merits further investigation as a surrogate biomarker for monitoring efficacy and tolerance after immunotherapy.
Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological ...limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome.
Although Foxp3
regulatory T cells (Tregs) require interleukin-2 (IL-2) for their development, it has been unclear whether continuing IL-2 signals are needed to maintain lineage stability, survival, ...and suppressor function in mature Tregs. We generated mice in which CD25, the main ligand-binding subunit of the IL-2 receptor, can be inducibly deleted from Tregs after thymic development. In contrast to Treg development, we find that IL-2 is dispensable for maintaining lineage stability in mature Tregs. Although continuous IL-2 signaling is needed for long-term Treg survival, CD25-deleted Tregs may persist for several weeks in vivo using IL-7. We also observe defects in glycolytic metabolism and suppressor function following CD25 deletion. Thus, unlike developing Tregs in which the primary role of IL-2 is to initiate Foxp3 expression, mature Tregs require continuous IL-2 signaling to maintain survival and suppressor function, but not to maintain lineage stability.
Summary
In the past decade, the power of harnessing T‐cell co‐signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has ...concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR‐Ts) and second, re‐animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re‐ignite T‐cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T‐cell co‐signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy's Yang, and focus on manipulating T‐cell co‐signaling to induce tolerance rather than activation. In this review, we discuss the major T‐cell signaling pathways that are being investigated for tolerance induction, detailing preclinical studies and the path to the clinic for many of these molecules. These include blockade of co‐stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector vs regulatory T‐cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.
Regulatory T cells (T
cells), a distinct subset of CD4
T cells, are necessary for the maintenance of immune self-tolerance and homeostasis
. Recent studies have demonstrated that T
cells exhibit a ...unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4
effector subsets
. Furthermore, the T
cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration
; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T
cells. Here we report that T
cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting T
cell number. Mice that lack mitochondrial complex III specifically in T
cells displayed a loss of T cell-suppression capacity without altering T
cell proliferation and survival. T
cells deficient in complex III showed decreased expression of genes associated with T
function, whereas Foxp3 expression remained stable. Loss of complex III in T
cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases
. Thus, T
cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
The intracellular signaling molecule TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC-specific deletion of TRAF6 (TRAF6ΔDC) resulted, ...unexpectedly, in loss of mucosal tolerance, characterized by spontaneous development of T helper 2 (Th2) cells in the lamina propria and eosinophilic enteritis and fibrosis in the small intestine. Loss of tolerance required the presence of gut commensal microbiota but was independent of DC-expressed MyD88. Further, TRAF6ΔDC mice exhibited decreased regulatory T (Treg) cell numbers in the small intestine and diminished induction of iTreg cells in response to model antigen. Evidence suggested that this defect was associated with diminished DC expression of interleukin-2 (IL-2). Finally, we demonstrate that aberrant Th2 cell-associated responses in TRAF6ΔDC mice could be mitigated via restoration of Treg cell activity. Collectively, our findings reveal a role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity.
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•Dendritic cell (DC)-expressed TRAF6 is critical for small intestine immune tolerance•Spontaneous gut Th2 cell responses develop in the absence of DC-expressed TRAF6•Gut microbiota trigger small intestine autoimmunity absent DC-expressed TRAF6•DC-expressed TRAF6 controls IL-2-associated iTreg cell induction in small intestine
CD4
Foxp3
regulatory T cells (Tregs) are an essential component of immune homeostasis. Modulation of Treg function has been proposed as a means of treating autoimmune conditions and preventing ...rejection of organ transplants, although achieving this goal will require a detailed understanding of Treg signaling pathways. Signaling within Tregs is known to differ considerably from that observed in other T cell subsets. Of note, Tregs are the only cell type known to constitutively express CD25, the main ligand-binding subunit of the IL-2 receptor. The PI(3)K/Akt/mTOR cascade constitutes a major signaling pathway downstream of IL-2 and is closely tied to cellular metabolism. Due to increasing recognition of the links between cellular fuel usage and immune cell function, the interplay between IL-2 signaling and Treg metabolism represents an important space for exploration and a potential approach for immunomodulation. Here, we discuss how IL-2 may affect Treg metabolism
PI(3)K signaling, as well as the effects of altered metabolism on Treg lineage stability and suppressor function.
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