Foxp3 regulates megakaryopoiesis and platelet function.
OBJECTIVE
Platelets are crucial for hemostasis and are vital regulators of inflammation. Foxp3 is a key transcription factor for T regulatory cell development. Humans with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, x-linked) and the scurfy (Foxp3(sf)) mouse have mutations in the Foxp3 gene that lead to a host of pathologies including autoimmunity and skin diseases. Scurfy mice and some humans with IPEX are also thrombocytopenic. The purpose of this study was to determine whether the absence of functional Foxp3 leads to defects in megakaryocytes and platelets.


RESULTS
We discovered that human and mouse megakaryocytes express Foxp3 mRNA and protein. Using shRNA and Foxp3(sf) mice, we demonstrated that Foxp3-deficient mouse and human megakaryocyte progenitors exhibited proliferation defects. Striking platelet abnormalities were observed in both an IPEX patient and Foxp3(sf) mice. Impaired platelet spreading and release of TGF-beta and CD40 ligand (CD40L), and abnormal levels of plasma CD40L were observed in a case of IPEX syndrome. Foxp3(sf) mice were thrombocytopenic and had increased platelet volume and altered serum levels of CD40L, TXB(2), and TGF-beta.


CONCLUSIONS
These findings provide compelling new evidence that Foxp3 is needed for proper megakaryopoiesis and plays a role in regulating platelet function including spreading and release.
Bernard
Jamie J
JJ
Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
Seweryniak
Kathryn E
KE
Koniski
Anne D
AD
Spinelli
Sherry L
SL
Blumberg
Neil
N
Francis
Charles W
CW
Taubman
Mark B
MB
Palis
James
J
Phipps
Richard P
RP
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D013045:Species Specificity; D034061:Thrombopoiesis / Q000502:physiology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D012333:RNA, Messenger