The Transcription Factor E4BP4 Is Not Required for Extramedullary Pathways of NK Cell Development
Author(s)
Type
Journal Article
Abstract
NK cells contribute to antitumor and antiviral immunosurveillance. Their development in the bone marrow (BM) requires the transcription factor E4BP4/NFIL3, but requirements in other organs are less well defined. In this study, we show that CD3−NK1.1+NKp46+CD122+ NK cells of immature phenotype and expressing low eomesodermin levels are found in thymus, spleen, and liver of E4BP4-deficient mice, whereas numbers of mature, eomesoderminhigh conventional NK cells are drastically reduced. E4BP4-deficient CD44+CD25− double-negative 1 thymocytes efficiently develop in vitro into NK cells with kinetics, phenotype, and functionality similar to wild-type controls, whereas no NK cells develop from E4BP4-deficient BM precursors. In E4BP4/Rag-1 double-deficient (DKO) mice, NK cells resembling those in Rag-1–deficient controls are found in similar numbers in the thymus and liver. However, NK precursors are reduced in DKO BM, and no NK cells develop from DKO BM progenitors in vitro. DKO thymocyte precursors readily develop into NK cells, but DKO BM transfers into nude recipients and NK cells in E4BP4/Rag-1/IL-7 triple-KO mice indicated thymus-independent NK cell development. In the presence of T cells or E4BP4-sufficient NK cells, DKO NK cells have a selective disadvantage, and thymic and hepatic DKO NK cells show reduced survival when adoptively transferred into lymphopenic hosts. This correlates with higher apoptosis rates and lower responsiveness to IL-15 in vitro. In conclusion, we demonstrate E4BP4-independent development of NK cells of immature phenotype, reduced fitness, short t1/2, and potential extramedullary origin. Our data identify E4BP4-independent NK cell developmental pathways and a role for E4BP4 in NK cell homeostasis.
Date Issued
2014-03-15
Date Acceptance
2014-01-09
Citation
JOURNAL OF IMMUNOLOGY, 2014, 192 (6), pp.2677-2688
ISSN
0022-1767
Publisher
American Association of Immunologists
Start Page
2677
End Page
2688
Journal / Book Title
JOURNAL OF IMMUNOLOGY
Volume
192
Issue
6
Copyright Statement
© 2014 The Authors This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license (https://creativecommons.org/licenses/by/3.0/).
Sponsor
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000332702700017&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
G0901737
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
NATURAL-KILLER-CELL
INNATE LYMPHOID-CELLS
MURINE BONE-MARROW
T-CELL
UNIQUE SUBSET
IDENTIFICATION
PROGENITORS
MATURATION
MICE
ACTIVATION
Publication Status
Published
Date Publish Online
2014-03-07