Relationships between early B- and NK-lineage lymphocyte precursors in bone marrow

Abstract

IntroductionNatural killer (NK) cells have long been recognized for their importance in innate immunity, viral defense, and tumor surveillance. 1 Additionally, NK cells represent barriers to bone marrow transplantation and produce cytokines that influence other cellular components of the immune system. Impressive progress has recently been made in understanding how NK cells recognize targets for cytolytic destruction while sparing normal cells. 2 For example, it is now clear that self-tolerance of NK cells is maintained by inhibitory receptors, which are expressed on NK cells and recognize major histocompatibility complex (MHC) class I molecules. In mice, the Ly49 receptor family recognizes classical MHC I molecules, whereas the CD94/NKG2 receptors recognize the nonclassical Qa-1 b MHC I molecule. Some additional NK molecules have been suggested to function as activating receptors. 3 Recent reports suggest that the self-recognizing NK-cell receptor repertoire is built in successive fashion following contact of NK-cell precursors with environmental class I MHC molecules during development. 3,4 However, many questions remain about the origin and lifespans of NK cells. Although still incomplete, a differentiation sequence is emerging that will eventually describe how hematopoietic stem cells generate NK cells in mice and humans. 5 Although cells with NK-lineage potential can be found among undifferentiated thymocytes, and some properties are shared with T cells, the thymus is probably not the most important site for production of NK cells. 6,7 The present study was designed to obtain more precise information about relationships between early NK-lineage precursors and those of other lymphoid lineages within bone marrow.The NK-1.1 antigen encoded by the NKR P1C gene provides a useful NK-cell marker in selected strains of mice, but is also expressed on a subset of T cells (NK T cells). The DX5 antigen, recently shown to be identical to CD49, is somewhat less restricted to NK-lineage cells, 8 and is probably acquired at a later stage. For example, there are NK-1.1 ϩ DX5 Ϫ cells in bone marrow, whereas most NK-1.1 ϩ spleen cells are DX5 ϩ . 9 It is interesting that fetal and neonatal NK cells express high levels of CD94/NKG2A receptors, but not Ly49. The density of CD94/NKG2A gradually declines when Ly49 family receptors are acquired. 10 Although interleukin 2 (IL-2) can be used to drive formation of NK cells in vitro, IL-2-deficient mice and IL-2 receptor ␣ chain (IL-2R␣)-deficient mice have NK cells. 11,12 In contrast, the IL-2R␤, the common ␥ chain (␥c) of the IL-2/IL-7 receptor and the tyrosine kinase JAK3 are all required for generation of NK cells. [13][14][15] First cloned from a human bone marrow stromal cell line, IL-15 uses a receptor composed of an IL-15-specific ␣ chain, the IL-2R␤, and the ␥c. for this cytokine were recently determined to be committed NK-cell progenitors. 9 Similar CD122 ϩ NK precursors can also be derived from multipotent Lin Ϫ Sca-2 ϩ c-kit ϩ progenitors in vitro. 23 Kondo and colleagues ...

Propensity of Adult Lymphoid Progenitors to Progress to DN2/3 Stage Thymocytes with Notch Receptor Ligation

“…Indeed, the Lin Ϫ c-Kit low Flk-2 ϩ prolymphocyte fraction of marrow is the best source of NK progenitors, and before acquisition of the CD122 receptor for IL-15, many of them still retain B lineage potential (39,40). We did not intentionally promote development of NK cells by addition of IL-15 in the present study.…”

Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells

“…3A, top panels). Production of the less B lineage-restricted category of CD45R ϩ CD19 ϩ/Ϫ CD11b/Mac-1 Ϫ cells (36,38) was also unaffected (Fig. 3A, lower panels).…”

Interferon-producing killer dendritic cells (IKDCs) arise via a unique differentiation pathway from primitive c-kitHiCD62L+ lymphoid progenitors

“…Lymphopoiesis is arrested by high estrogen concentrations, 16,17 while a population of estrogen-resistant common myeloid progenitors (CMPs) generate pDCs on transplantation, 30 and GM-CSFmediated differentiation of Langerhans cells is actually dependent on this hormone. 36 Therefore, estrogen treatment experiments were BLOOD, 1 JUNE 2007 ⅐ VOLUME 109, NUMBER 11 For personal use only.…”

“…15 All lymphoid progenitors in BM are rapidly and preferentially depleted in estrogen-treated mice. 16,17 Progenitors that can more quickly give rise to lymphocytes reside in a Lin Ϫ Flk-2 ϩ c-Kit Lo prolymphocyte (Pro-L) fraction that includes Lin Ϫ c-Kit Lo Sca-1 ϩ IL-7R␣ ϩ common lymphoid progenitors (CLPs). 16,18 While CLPs have some T-lineage potential under experimental circumstances, most of them appear to be biased toward B and NK lineages.…”

“…16,18 While CLPs have some T-lineage potential under experimental circumstances, most of them appear to be biased toward B and NK lineages. 14,17,[19][20][21] Although a bipotential T/NK progenitor is recognizable in fetal tissues, 22,23 the earliest steps in adult NK cell development appears to be shared with B lymphocytes. Cells in the Pro-L fraction may represent an important intermediate in the production of NK cells, as single cell analysis and 2-step cultures revealed that NK cells are made from segregating Pro-L whose fate is established with expression of CD122.…”