Cdc25A-driven proliferation regulates CD62L levels and lymphocyte movement in response to interleukin-7.
OBJECTIVE
Interleukin-7 (IL-7) is a multifunctional cytokine and a promising immunotherapeutic agent. However, because transient T-cell depletion is an immediate outcome of IL-7 administration at supraphysiological doses, we investigated the mechanism by which the IL-7 proliferative signal transduced through Cdc25A, a key activator of cyclin-dependent kinases, could modulate lymphocyte movement.


METHODS
Employing novel methods of manipulating Cdc25A gene expression, combined with in vitro and in vivo evaluation of IL-7 application, we assessed the expression of activation and homing markers and identified the mechanism by which IL-7 could induce T-cell expansion and alter lymphocyte motility.


RESULTS
Constitutively active Cdc25A drove T-cell proliferation independently of IL-7 and resulted in an activated phenotype (CD69(hi), CD44(hi)). Conversely, inhibition of Cdc25A resulted in decreased proliferation, reduced expression of activation markers, and upregulation of the lymph node homing molecule, CD62L, which promoted cell adhesion when engaged by ligand. We found that IL-7 prevented the nuclear translocation of the transcription factor, Foxo1, in a manner dependent on the activity of Cdc25A, resulting in decreased levels of CD62L. In vivo administration of IL-7 decreased lymph node cellularity, while treatment with IL-7, premixed with a neutralizing IL-7 antibody (M25), increased total lymph node cells--with more nuclear Foxo1 detected in cells from mice receiving IL-7 + M25.


CONCLUSIONS
These results are consistent with the model that IL-7 drives Cdc25A-mediated T-cell proliferation, which prevents the nuclear translocation of Foxo1, leading to reduced expression of CD62L and the migration of T cells into circulation.
Kittipatarin
Christina
C
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL 32827, USA.
Li
Wenqing
W
Durum
Scott K
SK
Khaled
Annette R
AR
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D015851:Interleukin-7 / Q000494:pharmacology*; D019041:L-Selectin / Q000032:analysis*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*
D015851:Interleukin-7; D019041:L-Selectin; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases