Abstract
Understanding of natural killer (NK) cell development in human is incomplete partly because of limited access to appropriate human tissues. We have developed a cytokine-enhanced humanized mouse model with greatly improved reconstitution and function of human NK cells. Here we report the presence of a cell population in the bone marrow of the cytokine-treated humanized mice that express both NK cell marker CD56 and myeloid markers such as CD36 and CD33. The CD56+CD33+CD36+ cells are also found in human cord blood, fetal and adult bone marrow. Although the CD56+CD33+CD36+ cells do not express the common NK cell functional receptors and exhibit little cytotoxic and cytokine-producing activities, they readily differentiate into mature NK cells by acquiring expression of NK cell receptors and losing expression of the myeloid markers. Further studies show that CD33+CD36+ myeloid NK precursors are derived from granulo-myelomonocytic progenitors. These results delineate the pathway of human NK cell differentiation from myeloid progenitors in the bone marrow and suggest the utility of humanized mice for studying human hematopoiesis.
Highlights
Studies have shown that natural killer (NK) cells can be differentiated from both lymphoid and myeloid progenitors
bone marrow (BM) NK cells were enriched for myeloid lineage marker expression, including CD33 and CD36, while the expression levels of NK cell functional receptors such as NKG2D, NKG2A and NKp46, were much lower than NK cells from spleen, liver and lung (Fig. 1B)
We identified an immature CD56+ NK cell population in the BM of humanized mice that expresses myeloid markers including CD36 and CD33 but not NK cell functional receptors such as NKG2D and NKp46
Summary
Studies have shown that NK cells can be differentiated from both lymphoid and myeloid progenitors. Based on CD34, CD117 and CD94 expression, human NK cell maturation in the secondary lymphoid tissues can be divided into four stages and CD33 expression is detected in the first three stages, but is lost upon maturation into CD56high NK cells[11] Despite these advances, our understanding of NK cell development in humans is still incomplete. We further show that these myeloid NK precursors can be derived from granulo-myelomonocytic progenitors (GMPs), and give rise to mature NK cells. These findings further delineate the pathway of human NK cell differentiation from myeloid progenitors in the BM and suggest the utility of humanized mice for studying the development of human NK and other immune cell types
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