Manipulating CD38 ectoenzymatic activity revitalizes regulatory T cells via deacetylase Sirt-1 in immune thrombocytopenia.

BACKGROUND

Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder where considerable dysfunction of regulatory T cells (Tregs) contributes to the loss of immune tolerance. CD38 is a transmembrane glycoprotein equipped with ectoenzymatic activities. It affects other NAD+-consuming enzymes such as deacetylase Sirtuin-1 (Sirt-1), which is pivotal for Treg stability. Anti-CD38 monoclonal antibodies exert ectoenzyme-modulating capacity and has been proven to rapidly boost and maintain platelet levels in patients with ITP.

OBJECTIVES

This study aimed to investigate the effect of CD38-targeted therapy on the functional reprogramming of Tregs in patients with ITP, including its molecular mechanisms associated with Sirt-1 in vitro and in vivo.

METHODS

Patient samples and a murine model of active ITP were subject to multiple interventions of Sirt-1 or Treg depletion, followed by integrative immunophenotyping by flow cytometry and transcriptome profiling. Here, anti-CD38 therapies were credited for an equally important mechanism to the depletion of plasma cells in autoimmune diseases.

RESULTS

Daratumumab promoted expansion of and enhanced the suppressive activity of Tregs from patients with ITP by blocking Sirt-1. Anti-CD38 therapy elevated global acetylation and intracellular NAD+ levels in Tregs and modified the immune landscape apart from alleviating thrombocytopenia in ITP mice. Transcriptome profiling of posttreatment murine Tregs elucidated altered epigenetic pathways and CBX3 as a Sirt-1 regulator. Depleting Tregs finally confirmed that Sirt-induced reprogramming was specific for Tregs.

CONCLUSION

This study suggests that manipulating the ectoenzymatic activity of CD38 holds potential to restore immune balance via Sirt-1, providing a novel target and rationalizing its long-term efficacy in patients with ITP.