Mitochondrial ROS-dependent CD4+PD-1+T cells are pathological expansion in patients with primary immune thrombocytopenia

• Published in: International immunopharmacology Vol. 122; p. 110597
• Main Authors: Li, Weiping, Bai, Ziran, Liu, Jiaqing, Tang, Yawei, Yin, Chunlai, Jin, Minli, Mu, Lijun, Li, Xia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2023
• Subjects: CD4+T cell; Immune thrombocytopenia (ITP); Mitochondrial reactive oxygen species (mtROS); PD-1; CD4+T cell; Mitochondrial reactive oxygen species (mtROS); PD-1; Immune thrombocytopenia (ITP); CD4(+)T cell
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.110597

•CD4+PD-1+T cells were potentially involved in ITP immunopathogenesis.•CD4+PD-1+T cells were not exhausted and retained cytokine-producing potential and positively correlated with the plasmablasts in ITP.•Increased mtROS was related to CD4+PD-1+T cell function. Aberrant-activated T cells, especially CD4+T cells, play a crucial part in the pathogenetic progress of immune thrombocytopenia (ITP). PD-1-mediated signals play a negative part in the activation of CD4+T cells. However, knowledge is limited on the pathogenic characteristics and function of CD4+PD-1+T cells in ITP. The frequency and phenotype including cell activation, apoptosis, and cytokine production of CD4+PD-1+T cells were evaluated by flow cytometry. PD-1 Ligation Assay was performed to assess the function of PD-1 pathway in CD4+T cells. Mitochondrial reactive oxygen species (mtROS) were detected by MitoSOX Red probe. Compared with healthy controls (HC), the frequencies of CD4+PD-1+T cells were significantly increased in ITP patients. However, these cells are not exhausted despite PD-1 expression. Besides retaining cytokine-producing potential, these CD4+PD-1+T cells also had a possible B-cell helper function including expressing ICOS, CD84, and CD40L. Moreover, the CD4+PD-1+T cell subset contained higher levels of mitochondrial ROS than CD4+PD-1-T cell subset in patients with ITP. And mtROS inhibition could reduce the secretion of the inflammatory cytokines and regulate the function of CD4+PD-1+T cells. Upon in-vitro T cell receptor (TCR) stimulation of CD4+T cells in the presence of plate-bound PD-L1 fusion protein (PD-L1-Ig), CD4+T cells from ITP patients appeared resistant to such PD-1-mediated inhibition of interferon (IFN)-γ secretion. The CD4+PD-1+T cells were more abundant in patients with ITP. Additionally, this CD4+PD-1+T cell subset may be a potential etiology of ITP and a potential immune therapeutic target for ITP patients in the future.