Dysregulation of apolipoprotein o reprograms CCR7+CD4+T cell fate in primary autoimmune thrombocytopenia

TL;DR

This study shows that a protein called APOO helps control the development of certain immune cells, and its dysfunction may lead to an autoimmune blood disorder.

Contribution

The paper identifies APOO as a novel metabolic-transcriptional checkpoint regulating CCR7+CD4+ T cell fate in autoimmune thrombocytopenia.

Findings

APOO downregulation in ITP CD4+CCR7+T cells reduces CCR7 and promotes SP100 expression.

APOO preserves oxidative metabolism and CCR7 identity in normal T cells.

APOO is hypermethylated and transcriptionally silenced in patient-derived CD4+ T cells.

Abstract

Primary immune thrombocytopenia involves antibody-driven platelet loss and perturbed CD4+ T cell regulation. By integrating single-cell transcriptomic, epigenetic, and functional analyses, we delineated CCR7+CD4+ T cell states with distinct metabolic and transcriptional programs. A subset enriched in patients exhibited reduced oxidative phosphorylation and enhanced glycolysis, accompanied by elevated expression of SP100 and its downstream transcriptional targets FOXP1 and CDK6. Trajectory analysis positioned these cells as developmentally arrested intermediates that, in normal individuals, mature into CCR7+ cells expressing apolipoprotein O (APOO). Functional perturbations revealed that APOO preserves oxidative metabolism and CCR7 identity while restraining SP100-dependent transcription. Methylation profiling identified APOO hypermethylation and transcriptional silencing in patient-derived CD4+ T cells. Together, these data define APOO as a metabolic-transcriptional checkpoint governing CCR7+CD4+ T cell fate, whose repression fosters dysfunctional differentiation and immune imbalance in autoimmune thrombocytopenia.

•ITP vs. Normal CD4+CCR7+T cells differ in transcription and metabolism•APOO is altered at transcript and methylation levels in ITP CD4+T cells•In ITP CD4+CCR7+T cells, APOO downregulation lowers CCR7 via OXPHOS and drives SP100•APOO acts as a dual metabolic-transcriptional checkpoint and potential ITP target

ITP vs. Normal CD4+CCR7+T cells differ in transcription and metabolism

APOO is altered at transcript and methylation levels in ITP CD4+T cells

In ITP CD4+CCR7+T cells, APOO downregulation lowers CCR7 via OXPHOS and drives SP100

APOO acts as a dual metabolic-transcriptional checkpoint and potential ITP target

Immunology; Hematology; Transcriptomics

Figures