@article{discovery10099372,
         journal = {The Journal of Immunology},
           title = {Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation},
            year = {2020},
           month = {May},
            note = {{\copyright} 2020 The Authors. This article is distributed under the terms of the CC BY 4.0 Unported license (https://creativecommons.org/licenses/by/4.0/).},
          author = {Stark, A-K and Davenport, ECM and Patton, DT and Scudamore, CL and Vanhaesebroeck, B and Veldhoen, M and Garden, OA and Okkenhaug, K},
             url = {https://doi.org/10.4049/jimmunol.2000043},
        abstract = {Class I PI3K enzymes are critical for the maintenance of effective immunity. In T cells, PI3K{\ensuremath{\alpha}} and PI3K{\ensuremath{\delta}} are activated by the TCR and costimulatory receptors, whereas PI3K{\ensuremath{\gamma}} is activated by G protein-coupled chemokine receptors. PI3K{\ensuremath{\delta}} is a key regulator of regulatory T (Treg) cell function. PI3K isoform-selective inhibitors are in development for the treatment of diseases associated with immune dysregulation, including chronic inflammatory conditions, cancer, and autoimmune diseases. Idelalisib (PI3K{\ensuremath{\delta}}), alpelisib (PI3K{\ensuremath{\alpha}}), duvelisib (PI3K{\ensuremath{\delta}}/{\ensuremath{\gamma}}), and copanlisib (pan-PI3K) have recently been approved for use in cancer treatment. Although effective, these therapies often have severe side effects associated with immune dysregulation and, in particular, loss of Treg cells. Therefore, it is important to gain a better understanding of the relative contribution of different PI3K isoforms under homeostatic and inflammatory conditions. Experimental autoimmune encephalitis is a mouse model of T cell-driven CNS inflammation, in which Treg cells play a key protective role. In this study, we show that PI3K{\ensuremath{\delta}} is required to maintain normal Treg cell development and phenotype under homeostatic conditions but that loss of PI3K{\ensuremath{\delta}} alone in Treg cells does not lead to autoimmunity. However, combined loss of PI3K{\ensuremath{\alpha}} and PI3K{\ensuremath{\delta}} signaling resulted in increased experimental autoimmune encephalitis disease severity. Moreover, mice lacking PI3K{\ensuremath{\alpha}} and PI3K{\ensuremath{\delta}} in Treg cells developed spontaneous peripheral nerve inflammation. These results show a key role for PI3K signaling in Treg cell-mediated protection against CNS inflammation.},
            issn = {0022-1767}
}