TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL

Blood. 2017 Aug 24;130(8):982-994. doi: 10.1182/blood-2017-03-770982. Epub 2017 Jul 10.

Abstract

As with many immunopathologically driven diseases, the malignant T cells of cutaneous T-cell lymphomas (CTCLs), such as Sézary syndrome, display aberrant cytokine secretion patterns that contribute to pathology and disease progression. Targeting this disordered release of cytokines is complicated by the changing cytokine milieu that drives the phenotypic changes of CTCLs. Here, we characterize a novel signaling pathway that can be targeted to inhibit the secretion of cytokines by modulating either CXCR4 or CXCR4-mediated signaling. We demonstrate that upon ligation of the T-cell antigen receptor (TCR), the TCR associates with and transactivates CXCR4 via phosphorylation of S339-CXCR4 in order to activate a PREX1-Rac1-signaling pathway that stabilizes interleukin-2(IL-2), IL-4, and IL-10 messenger RNA (mRNA) transcripts. Pharmacologic inhibition of either TCR-CXCR4 complex formation or PREX1-Rac1 signaling in primary human T cells decreased mRNA stability and inhibited secretion of IL-2, IL-4, and IL-10. Applying this knowledge to Sézary syndrome, we demonstrate that targeting various aspects of this signaling pathway blocks both TCR-dependent and TCR-independent cytokine secretion from a Sézary syndrome-derived cell line and patient isolates. Together, these results identify multiple aspects of a novel TCR-CXCR4-signaling pathway that could be targeted to inhibit the aberrant cytokine secretion that drives the immunopathogenesis of Sézary syndrome and other immunopathological diseases.

MeSH terms

  • Benzylamines
  • Cyclams
  • Cytokines / genetics*
  • Cytokines / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Jurkat Cells
  • Lymphocyte Subsets / drug effects
  • Lymphocyte Subsets / metabolism
  • Lymphoma, T-Cell, Cutaneous / metabolism*
  • Lymphoma, T-Cell, Cutaneous / pathology
  • Models, Biological
  • RNA Stability* / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, CXCR4 / metabolism*
  • Sezary Syndrome / pathology
  • Signal Transduction* / drug effects
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Benzylamines
  • CXCR4 protein, human
  • Cyclams
  • Cytokines
  • Guanine Nucleotide Exchange Factors
  • Heterocyclic Compounds
  • PREX1 protein, human
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • Receptors, CXCR4
  • rac1 GTP-Binding Protein
  • plerixafor