microRNA 184 regulates expression of NFAT1 in umbilical cord blood CD4+ T cells.
The reduced expression of nuclear factor of activated T cells-1 (NFAT1) protein in umbilical cord blood (UCB)-derived CD4+ T cells and the corresponding reduction in inflammatory cytokine secretion after stimulation in part underlies their phenotypic differences from adult blood (AB) CD4+ T cells. This muted response may contribute to the lower incidence and severity of high-grade acute graft-versus-host disease (aGVHD) exhibited by UCB grafts. Here we provide evidence that a specific microRNA, miR-184, inhibits NFAT1 protein expression elicited by UCB CD4+ T cells. Endogenous expression of miR-184 in UCB is 58.4-fold higher compared with AB CD4+ T cells, and miR-184 blocks production of NFAT1 protein through its complementary target sequence on the NFATc2 mRNA without transcript degradation. Furthermore, its negative effects on NFAT1 protein and downstream interleukin-2 (IL-2) transcription are reversed through antisense blocking in UCB and can be replicated via exogenous transfection of precursor miR-184 into AB CD4+ T cells. Our findings reveal a previously uncharacterized role for miR-184 in UCB CD4+ T cells and a novel function for microRNA in the early adaptive immune response.
Weitzel
R Patrick
RP
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Lesniewski
Mathew L
ML
Haviernik
Peter
P
Kadereit
Suzanne
S
Leahy
Patrick
P
Greco
Nicholas J
NJ
Laughlin
Mary J
MJ
D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000367:Age Factors; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D035683:MicroRNAs / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D020413:3' Untranslated Regions; D007376:Interleukin-2; C534424:MIRN184 microRNA, human; D035683:MicroRNAs; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D012333:RNA, Messenger