| First Author | Stark AK | Year | 2020 |
| Journal | J Immunol | Volume | 205 |
| Issue | 1 | Pages | 78-89 |
| PubMed ID | 32414808 | Mgi Jnum | J:291916 |
| Mgi Id | MGI:6445020 | Doi | 10.4049/jimmunol.2000043 |
| Citation | Stark AK, et al. (2020) Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation. J Immunol 205(1):78-89 |
| abstractText | Class I PI3K enzymes are critical for the maintenance of effective immunity. In T cells, PI3Kalpha and PI3Kdelta are activated by the TCR and costimulatory receptors, whereas PI3Kgamma is activated by G protein-coupled chemokine receptors. PI3Kdelta 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 (PI3Kdelta), alpelisib (PI3Kalpha), duvelisib (PI3Kdelta/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 PI3Kdelta is required to maintain normal Treg cell development and phenotype under homeostatic conditions but that loss of PI3Kdelta alone in Treg cells does not lead to autoimmunity. However, combined loss of PI3Kalpha and PI3Kdelta signaling resulted in increased experimental autoimmune encephalitis disease severity. Moreover, mice lacking PI3Kalpha and PI3Kdelta 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. |
