Expression of BMPRIA on human thymic NK cell precursors: role of BMP signaling in intrathymic NK cell development.
The bone morphogenetic protein (BMP) signaling pathway regulates survival, proliferation, and differentiation of several cell types in multiple tissues, including the thymus. Previous reports have shown that BMP signaling negatively regulates T-cell development. Here, we study the subpopulation of early human intrathymic progenitors expressing the type IA BMP receptor (BMPRIA) and provide evidence that CD34(+)CD1a(-)BMPRIA(+) precursor cells mostly express surface cell markers and transcription factors typically associated with NK cell lineage. These CD34(+) cells mostly differentiate into functional CD56(+) natural killer (NK) cells when they are cocultured with thymic stromal cells in chimeric human-mouse fetal thymic organ cultures and also in the presence of SCF and IL-15. Moreover, autocrine BMP signaling can promote the differentiation of thymic NK cells by regulating the expression of key transcription factors required for NK cell lineage (eg, Id3 and Nfil3) as well as one of the components of IL-15 receptor, CD122. Subsequently, the resulting population of IL-15-responsive NK cell precursors can be expanded by IL-15, whose action is mediated by BMP signaling during the last steps of thymic NK cell differentiation. Our results strongly suggest that BMPRIA expression identifies human thymic NK cell precursors and that BMP signaling is relevant for NK cell differentiation in the human thymus.
Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain.
Laura
L
Hidalgo
Víctor G
VG
Martínez
Jaris
J
Valencia
Carmen
C
Hernández-López
Miriam N
MN
Vázquez
José R
JR
Nuñez
Agustín G
AG
Zapata
Rosa
R
Sacedón
Alberto
A
Varas
Angeles
A
Vicente
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D019002:CD56 Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D002675:Child, Preschool; D018920:Coculture Techniques; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism / Q000648:ultrastructure; D016130:Immunophenotyping; D007223:Infant; D019409:Interleukin-15 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008854:Microscopy, Electron; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D060168:Thymocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology
D018952:Antigens, CD34; D055415:Bone Morphogenetic Protein 4; D019002:CD56 Antigen; D019409:Interleukin-15; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I