Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation

Stark, Anne-Katrien; Davenport, Elizabeth C M; Patton, Daniel T.; Scudamore, Cheryl L.; Vanhaesebroeck, Bart; Veldhoen, Marc; Garden, Oliver A.; Okkenhaug, Klaus

doi:10.4049/jimmunol.2000043

Cited by 19 publications

(27 citation statements)

References 59 publications

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“…As in any intervention that may modulate Treg function, tumor-specific approaches are desirable to avoid autoimmune sequelae as much as possible. Indeed, systemic inhibition of p110δ in Tregs has recently been associated with autoimmunity in mouse models 78 and has also been reported in clinical settings of PI3K use.…”

Section: Modulation Of Pi3k To Improve Efficacy Of Immunotherapymentioning

confidence: 91%

Control of T lymphocyte fate decisions by PI3K signaling

Murter

Kane

2020

F1000Res

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Virtually all aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments. Antigen receptors mediate their effects by modulating intracellular signaling pathways that ultimately impinge on the cytoskeleton, bioenergetic pathways, transcription, and translation. Although these signaling pathways are rather well described at this point, especially those steps that are most receptor-proximal, how such pathways contribute to more quantitative aspects of lymphocyte function is still being elucidated. One of the signaling pathways that appears to be involved in this “tuning” process is controlled by the lipid kinase PI3K. Here we review recent key findings regarding both the triggering/enhancement of PI3K signals (via BCAP and ICOS) as well as their regulation (via PIK3IP1 and PHLPP) and how these signals integrate and determine cellular processes. Lymphocytes display tremendous functional plasticity, adjusting their metabolism and gene expression programs to specific conditions depending on their tissue of residence and the nature of the infectious threat to which they are responding. We give an overview of recent findings that have contributed to this model, with a focus on T cells, including what has been learned from patients with gain-of-function mutations in PI3K as well as lessons from cancer immunotherapy approaches.

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Section: Modulation Of Pi3k To Improve Efficacy Of Immunotherapymentioning

confidence: 91%

Control of T lymphocyte fate decisions by PI3K signaling

Murter

Kane

2020

F1000Res

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“…PI3K activity is crucial for the maintenance of effective immunity and Treg suppressive function in both mouse models and human cells ( 63 , 64 ). Mice lacking PI3K in Tregs display spontaneous peripheral nerve inflammation in the experimental autoimmune encephalomyelitis model ( 65 ). TGF-β is essential for pTregs to differentiate from naive CD4 + T cells and to maintain Treg homeostasis ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism

Gong

Park

et al. 2021

JCI Insight

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Estrogen-related receptor gamma (Esrrg) is a murine lupus susceptibility gene associated with T cell activation. Here, we report that Esrrg controls regulatory T cells (Treg) through mitochondria homeostasis. Esrrg deficiency impaired the maintenance and function of Treg cells, leading to global T cell activation and autoimmunity in aged mice. Further, Esrrg-deficient Treg cells presented an impaired differentiation into follicular Treg (Tfr) cells that enhanced follicular helper T cells (Tfh) responses. Mechanistically, Esrrg-deficient Treg cells presented with dysregulated mitochondria with decreased oxygen consumption as well as ATP and NAD + production. In addition, Esrrg-deficient Treg cells exhibited decreased phosphatidylinositol and TGF-β signaling pathways and increased mTORC1 activation. We found that the expression of human ESRRG, which is high in Treg cells, was lower in CD4 + T cells from lupus patients than in healthy controls.Finally, knocking down ESRRG in Jurkat T cells decreased their metabolism. Together, our results reveal a critical role of Esrrg in the maintenance and metabolism of Treg cells, which may provide a genetic link between lupus pathogenesis and mitochondrial dysfunction in T cells.

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“…The loss of T FH cells is the main reason underpinning the lack of germinal centres and immunoglobulin class switching after immunisation of PI3Kd-deficient mice (16). PI3Kd also regulates the differentiation of other T H subsets, including T H 1, T H 2, T H 17, and T reg , as well as production of cytokines and granzymes in both CD4 + and CD8 + T cells (15,(18)(19)(20)(21)(22)(23)(24)(25)(26). Human patients with loss of function mutations in PI3Kd have also been identified (27)(28)(29)(30).…”

Section: Pi3k In T Cell Developmentmentioning

confidence: 99%

PI3K in T Cell Adhesion and Trafficking

Johansen

Golec²,

Thomsen

et al. 2021

Front. Immunol.

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PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. Furthermore, characterisation of patients with Activated PI3K Delta Syndrome (APDS) and mouse models with hyperactive PI3Kδ have shed light on how increased PI3Kδ activity affects T cell functions. An important function of PI3Kδ is that it acts downstream of TCR stimulation to activate the major T cell integrin, LFA-1, which controls transendothelial migration of T cells as well as their interaction with antigen-presenting cells. PI3Kδ also suppresses the cell surface expression of CD62L and CCR7 which controls the migration of T cells across high endothelial venules in the lymph nodes and S1PR1 which controls lymph node egress. Therefore, PI3Kδ can control both entry and exit of T cells from lymph nodes as well as the recruitment to and retention of T cells within inflamed tissues. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function.

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Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation

Cited by 19 publications

References 59 publications

Control of T lymphocyte fate decisions by PI3K signaling

Control of T lymphocyte fate decisions by PI3K signaling

Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism

PI3K in T Cell Adhesion and Trafficking

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