CD4؉ CD25

Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

Clinical studies using bone marrowderived proangiogenic cells (PACs) have demonstrated modest improvements of function and/or perfusion of ischemic myocardium or skeletal muscle. Because the identities of these PACs and their functional ability to promote neovascularization remain poorly understood, it is possible that a subset of robust PACs exists but is obscured by the heteroge- IntroductionTherapeutic angiogenesis has emerged as an innovative strategy for the treatment of patients with cardiovascular ischemic disease states, such as myocardial ischemia or peripheral artery disease. Several clinical trials using autologous, bone marrow (BM)-derived mononuclear cells have demonstrated only modest improvements of function and/or perfusion of ischemic myocardium or limb in patients. [1][2][3][4][5][6] However, the identities of these BM-derived mononuclear cells and their functional ability to promote neovascularization remain poorly understood.Accumulating evidence has indicated that proangiogenic cells (PACs) may originate from the BM and are capable of being recruited to sites of ischemic injury, where they contribute to neovascularization and tissue repair through paracrine/autocrine mechanisms or by direct incorporation into the vessel wall. [7][8][9][10] Indeed, PAC function and/or number have been found to be markedly impaired in patients with coronary or peripheral artery disease. 11-17 Herein, we provide evidence that a hierarchy exists among mouse hematopoietic stem cell (HSC) progenitors in their ability to differentiate into PACs and promote neovascularization. Complementary functional studies revealed that common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) preferentially differentiate into PACs as opposed to megakaryocyte-erythrocyte progenitors (MEPs), HSCs, and common lymphoid progenitors. Moreover, only PACs derived from BM-derived CMPs and GMPs were able to enhance neovascularization in vivo. Taken together, these findings reveal a novel and unexpected hierarchy among BM-derived progenitors in their ability to promote neovascularization. Methods Isolation and in vitro culture of PACsProgenitor cells were isolated from C57BL/6 mice (n ϭ 8-10) BM by using multicolor FACSAria (BD Biosciences) as previously described. 18,19 Briefly, approximately 2 to 5 ϫ 10 5 BM-derived cells were prospectively isolated and purified as follows: HSCs (Lin Ϫ Sca1 ϩ c-kit ϩ ), CMPs (Lin Ϫ Sca1 Ϫ ckit ϩ CD34 ϩ Fc␥RII/II lo ), GMPs (Lin Ϫ Sca1 Ϫ c-kit ϩ CD34 ϩ Fc␥RII/III hi ), and MEPs (Lin Ϫ Sca1 Ϫ c-kit ϩ CD34 Ϫ Fc␥RII/III lo ; supplemental Figure 1A, available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Subsequently, cells were incubated in endothelial growth media-2 (EGM-2; Lonza) for 8 to 10 days and subjected to flow cytometry to detect expression of vascular endothelial growth factor receptor-2 (VEGFR2), CD31, CD133, CD34, CD45, Tie2, von Willebrand factor, endothelial nitric oxide synthase, and VE-cadherin (eBioscience). Cells were a...