AKT Hyperphosphorylation and T Cell Exhaustion in Down Syndrome

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• Down syndrome (DS) is linked to increased infections, autoimmunity, and malignancies.
• The underlying immunological mechanisms in DS remain poorly understood.
• DS shares features with Activated PI3K Delta Syndrome (APDS), characterized by PI3K/AKT/mTOR pathway overactivation.

Purpose of the Study:

• To investigate T cell exhaustion and AKT pathway hyperactivation in immune cells of children with Down syndrome.
• To compare the immunophenotype and signaling pathways in children with DS versus healthy controls.

Main Methods:

• Observational cohort study involving children with DS (n=22) and age-matched controls (n=21).
• Flow cytometry for immunophenotyping, phospho-flow AKT analysis, and T cell exhaustion markers.
• Analysis of T cells (CD3+, CD4+, CD8+), B cells (CD20+), and NK cells.

Main Results:

• Children with DS had lower absolute counts of transitional B cells, naive memory B cells, and naive CD4+/CD8+ T cells.
• Increased phosphorylated AKT (pAKT) and total AKT were observed in CD3+, CD4+, and CD20+ cells, and total AKT in CD8+ cells from children with DS.
• Elevated expression of inhibitory markers (PD-1, CD244, CD160) on CD4+ and CD8+ T cells indicated T cell exhaustion in DS.

Conclusions:

• Children with Down syndrome display heightened AKT signaling and T cell exhaustion.
• These immunological alterations may contribute to the increased risk of infections, autoimmunity, and hematological malignancies observed in DS.