TY - JOUR
T1 - TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway
T2 - Implications for CTCL
AU - Kremer, Kimberly N.
AU - Dinkel, Brittney A.
AU - Sterner, Rosalie M.
AU - Osborne, Douglas G.
AU - Jevremovic, Dragan
AU - Hedin, Karen E.
N1 - Funding Information:
This work was supported in part by the Joanne G. and Gary N. Owen Fund in Immunology Research, the Alma B. Stevenson Endowment Fund for Medical Research, and by National Institutes of Health (NIH) National Institute of General Medical Sciences grant RO1GM59763 (K.E.H.) and National Institute of Allergy and Infectious Diseases grant T32-AI07047 (D.G.O.). R.M.S. was supported by the Mayo Clinic Medical Scientist Training Program Robert L. Howell Physician-Scientist Scholarship. B.A.D. was supported by the NIH National Institute of Allergy and Infectious Diseases Ph.D. training grant in Basic Immunology (T32 AI07425) and the Mayo Clinic Graduate School of Biomedical Sciences (MCGSBS).
PY - 2017/8/24
Y1 - 2017/8/24
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2017-03-770982
DO - 10.1182/blood-2017-03-770982
M3 - Article
C2 - 28694325
AN - SCOPUS:85028465661
SN - 0006-4971
VL - 130
SP - 982
EP - 994
JO - Blood
JF - Blood
IS - 8
ER -