Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells

Abstract

BackgroundPatients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia.ObjectivesBecause regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]).MethodsPatients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3)+ Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse.ResultsAutoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4+ T-cell reduction, and changes in T- and B-cell subsets. Although total CD4+FOXP3+ Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3+ T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse.ConclusionHeterozygous loss of function of PTEN in human subjects has a significant effect on T- and B-cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency.

T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains

“…Autism Cases A2 ( PTEN megalencephaly) and A4 (XYY) were affected by the same T‐lymphocyte and astroglial neuropathology as the idiopathic ASD cases. Importantly, PTEN heterozygosity is associated with lymphoid hyperplasia and an increased risk of autoimmune disease in human and mouse . Similarly, XYY is a genetic defect reported in ASD cohorts, and genes on the Y chromosome have been connected to an increased risk of immunologic disease .…”

“…Importantly, PTEN heterozygosity is associated with lymphoid hyperplasia and an increased risk of autoimmune disease in human and mouse. 26,27 Similarly, XYY is a genetic defect reported in ASD cohorts, 28 and genes on the Y chromosome have been connected to an increased risk of immunologic disease. 29 By contrast, ASD Case A1 (mutations in ARID1B, CACNA1C, and SLC6A8), ASD Case A3 (mutation in SETD2), ASD Case A5 (dup15q), and another~30% of the ASD cases that are genetically undefined lacked features of the T-lymphocyte and astroglial neuropathology, suggesting behavioral deficits in these genetic subsets of ASD might instead arise from direct effects of the genetic or epigenetic changes on the neuronal circuits controlling behaviors impaired in ASD.…”

Gut microbiome and chronic prostatitis/chronic pelvic pain syndrome

“…In vitro, quercetin has been shown to increase PTEN expression and downregulate the AKT pathway (64). As has been recently shown, PTEN plays a role in development of the immune system (65,66). Similarly, diet and obesity have been shown to be associated with imbalances in the gut microbiome (67,68).…”

PTEN at the interface of immune tolerance and tumor suppression

“…A recent investigation of the immunological phenotype in PHTS patients provides a direct clinical correlate to these findings. Seventy nine patients with germline heterozygous mutations of PTEN were evaluated, and 43% of them were found to manifest some form of autoimmunity, lymphoid hyperplasia or both (Chen et al, 2016). Collectively, these findings implicate a dual role of PTEN in both tumor suppression and immune tolerance, and they underscore the relevance of exploring PTEN function in immune regulation.…”