Abstract
Class I PI3K enzymes are critical for the maintenance of effective immunity. In T cells, PI3Kα and PI3Kδ are activated by the TCR and costimulatory receptors, whereas PI3Kγ is activated by G protein-coupled chemokine receptors. PI3Kδ 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 (PI3Kδ), alpelisib (PI3Kα), duvelisib (PI3Kδ/γ), 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 PI3Kδ is required to maintain normal Treg cell development and phenotype under homeostatic conditions but that loss of PI3Kδ alone in Treg cells does not lead to autoimmunity. However, combined loss of PI3Kα and PI3Kδ signaling resulted in increased experimental autoimmune encephalitis disease severity. Moreover, mice lacking PI3Kα and PI3Kδ 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.
Highlights
Inactivation of PI3Kd by point mutation (p110dD910A/D910A) or by administration of the PI3Kd-selective inhibitor IC87114 did not alter the progression of MOG[35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]–induced EAE compared with wild-type or vehicle-treated mice (Fig. 1A)
Naive T cells from p110dD910A/D910A mice were less able to differentiate into Th1, Th17, or regulatory T (Treg) cells in vitro compared with wild-type T cells (Fig. 1C)
Analysis of CD4+ T cells infiltrating the spinal cord at peak disease severity showed that there was a trend toward increased proportions of total CD4+ T cells in FYC-p110afldfl mice and that this was associated with a significant reduction in the proportion of CD4+Foxp3+ Treg cells (Fig. 2B)
Summary
The analysis of CD4+ T cells present in the draining lymph nodes and spinal cord of p110dD910A/D910A mice during peak disease severity (day 15) showed reduced proportions of IFN-g– and IL-17–producing cells compared with wild-type littermate controls (Fig. 1B). Analysis of CD4+ T cells infiltrating the spinal cord at peak disease severity (day 16) showed that there was a trend toward increased proportions of total CD4+ T cells in FYC-p110afldfl mice and that this was associated with a significant reduction in the proportion of CD4+Foxp3+ Treg cells (Fig. 2B).
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