AKT Hyperphosphorylation and T Cell Exhaustion in Down Syndrome.

Daphne Peeters,Mirjam Van Der Burg,Roos Cuperus,Madelon Ruige,Frank Froeling,Mandana Rad,Gerda W Zijp,Gertjan J A Driessen,Ingrid Pico-Knijnenburg,Douwe Wieringa

doi:10.3389/fimmu.2022.724436

Daphne Peeters, Mirjam Van Der Burg + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2022.724436

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Abstract

Down syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is still unclear. The immunophenotype and clinical characteristics of DS resemble those of Activated PI3K Delta Syndrome (APDS), in which the PI3K/AKT/mTOR pathway is overactivated. We hypothesized that T cell exhaustion and the hyperactivation of the AKT signalling pathway is also present in immune cells of children with DS. In this observational non-interventional cohort study we collected blood samples of children with DS (n=22) and healthy age-matched controls (n=21) for flowcytometric immunophenotyping, phospho-flow AKT analysis and exhaustion analysis of T cells. The median age was 5 years (range 1-12y). Total T and NK cells were similar for both groups, but absolute values and transitional B cells, naive memory B cells and naive CD4+ and CD8+ T cells were lower in DS. pAKT and AKT were increased for CD3+ and CD4+ T cells and CD20+ B cells in children with DS. Total AKT was also increased in CD8+ T cells. Children with DS showed increased expression of inhibitory markers Programmed cell dealth-1 (PD-1), CD244 and CD160 on CD8+ T cells and increased PD-1 and CD244+ expression on CD4+ T cells, suggesting T cell exhaustion. Children with DS show increased pAKT and AKT and increased T cell exhaustion, which might contribute to their increased susceptibility to infections, auto immunity and haematological malignancies.

Highlights

Trisomy 21 is the most common chromosomal abnormality and is associated with a variety of clinical conditions, including cardiac pathology, auto-immunity, immunodeficiency, haematological malignancy and neurological abnormalities such as early dementia [1,2,3,4]
We hypothesized that the AKT/mTOR pathway is hyperactivated in lymphocytes of patients with Down syndrome (DS), which might offer an explanation for the observed T cell exhaustion, immunodeficiency and immune dysregulation
In order to identify possible immunological alterations that could contribute to the clinical phenotype of children with Down syndrome, we explored the extent of hyperphosphorylation of the PI3K/AKT signalling pathway and T cell exhaustion and compared this with healthy age-matched individuals

Summary

Introduction

Trisomy 21 is the most common chromosomal abnormality and is associated with a variety of clinical conditions, including cardiac pathology, auto-immunity, immunodeficiency, haematological malignancy and neurological abnormalities such as early dementia [1,2,3,4]. The combination immunodeficiency, autoimmunity, the propensity to develop haematological malignancies and T cell anergy/exhaustion has previously been described in the primary immunodeficiency activated PI3K Delta Syndrome (APDS) [8,9,10,11]. In this primary immunodeficiency the PI3K/AKT/mTOR pathway is overly activated. Increased intracellular AKT-activity stimulates metabolism, cell proliferation, survival and growth and at the same time deregulates the humoral immune response and induces T cell anergy Hyperactivation of this pathway has been reported in the frontal cortex of individuals with DS who suffer from early dementia when compared to controls [12]. Our aim was to explore the extent of T cell exhaustion and hyperphosphorylation of the PI3K/AKT pathway in children with DS compared to healthy age-matched individuals

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