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, Karen Elaine Hedin

Research output: Contribution to journalArticle

4 Citations (Scopus)

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,wecharacterize 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 aSézary 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.

Original languageEnglish (US)
Pages (from-to)982-994
Number of pages13
JournalBlood
Volume130
Issue number8
DOIs
StatePublished - Aug 24 2017

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Cutaneous T-Cell Lymphoma
T-cells
T-Cell Antigen Receptor
Cytokines
Messenger RNA
Interleukin-4
Interleukin-10
Interleukin-2
T-Lymphocytes
Phosphorylation
RNA Stability
Pathology
Ligation
Disease Progression
Cells
Cell Line

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway : Implications for CTCL. / Kremer, Kimberly N.; Dinkel, Brittney A.; Sterner, Rosalie M.; Osborne, Douglas G.; Jevremovic, Dragan; Hedin, Karen Elaine.

In: Blood, Vol. 130, No. 8, 24.08.2017, p. 982-994.

Research output: Contribution to journalArticle

Kremer, Kimberly N. ; Dinkel, Brittney A. ; Sterner, Rosalie M. ; Osborne, Douglas G. ; Jevremovic, Dragan ; Hedin, Karen Elaine. / TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway : Implications for CTCL. In: Blood. 2017 ; Vol. 130, No. 8. pp. 982-994.
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