Hydroxychloroquine inhibits calcium signals in T cells: A new mechanism to explain its immunomodulatory properties

Academic Article

Abstract

  • Hydroxychloroquine (HCQ), a lysosomotropic amine, is an immunosuppressive agent presently being evaluated in bone marrow transplant patients to treat graft-versus-host disease. While its immunosuppressive properties have been attributed primarily to its ability to interfere with antigen processing, recent reports demonstrate HCQ also blocks T-cell activation in vitro. To more precisely define the T-cell inhibitory effects of HCQ, the authors evaluated T-cell antigen receptor (TCR) signaling events in a T-cell line pretreated with HCQ. In a concentration-dependent manner, HCQ inhibited anti-TCR-induced up-regulation of CD69 expression, a distal TCR signaling event. Proximal TCR signals, including inductive protein tyrosine phosphorylation, tyrosine phosphorylation of phospholipase C γ1, and total inositol phosphate production, were unaffected by HCQ. Strikingly, anti-TCR- crosslinking-induced calcium mobilization was significantly inhibited by HCQ, particularly at the highest concentrations tested (100 μmol/L) in both T- cell lines and primary T cells. HCQ, in a dose-dependent fashion, also reduced a B-cell antigen receptor calcium signal, indicating this effect may be a general property of HCQ. Inhibition of the calcium signal correlated directly with a reduction in the size of thapsigargin-sensitive intracellular calcium stores in HCQ-treated cells. Together, these findIngs suggest that disruption of TCR-crosslinking-dependent calcium signaling provides an additional mechanism to explain the immunomodulatory properties of HCQ. (C) 2000 by The American Society of Hematology.
  • Author List

  • Goldman FD; Gilman AL; Hollenback C; Kato RM; Premack BA; Rawlings DJ
  • Start Page

  • 3460
  • End Page

  • 3466
  • Volume

  • 95
  • Issue

  • 11