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

Kimberly N. Kremer, Brittney A. Dinkel, Rosalie M. Sterner, Douglas G. Osborne, Dragan Jevremovic and Karen E. Hedin

Key points

  • T cell activation induces TCR transactivation of CXCR4 to stabilize cytokine mRNA transcripts via a PREX1-Rac1 signaling pathway.

  • Inhibition of the TCR-CXCR4 signaling pathway impairs TCR-dependent and TCR-independent cytokine secretion by CTCL cells.

Abstract

As with many immunopathologically-driven diseases, the malignant T cells of cutaneous T cell lymphomas (CTCL), such as Sezary 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 CTCL. 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 TCR, the TCR associates with and transactivates CXCR4 via phosphorylation of S339-CXCR4 in order to activate a PREX1-Rac1 signaling pathway that stabilizes IL-2, IL-4, and IL-10 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 Sezary Syndrome, we demonstrate that targeting various aspects of this signaling pathway blocks both TCR-dependent and TCR-independent cytokine secretion from a Sezary 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 Sezary Syndrome and other immunopathological diseases.

  • Submitted March 1, 2017.
  • Accepted July 5, 2017.