CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells

Fu, Binqing; Wang, Fuyan; Sun, Rui; Ling, Bin; Tian, Zhigang; Wei, Haiming

doi:10.1111/j.1365-2567.2011.03446.x

Cited by 172 publications

(167 citation statements)

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“…This finding is in line with the downregulation of NKG2D observed in human NK cells upon CMV infection and suggests that the enhanced degranulation of NK cells (Fig. 5A) is due to a non-NKG2D-dependant pathway [20].The NK-cell maturation status can be characterized by the expression of CD11b and CD27 [21,22]. CD11b low CD27 low defines immature and naive NK cells, whereas CD11b high CD27 high NK cells represent the most potent effector cells and the CD11b high CD27 low the terminally differentiated NK cells.…”

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Adiponectin modulates NK‐cell function

et al. 2013

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Adiponectin (APN) has been shown to exert antiinflammatory effects in various disease models but little is known concerning its regulation of NK-cell function. Here, weshow that the majority of human CD56 dim NK cells express surface Adiponectin receptor (AdipoR) 1 and 2 while most CD56 high NK cells are AdipoR-negative. Toll-like receptor (TLR) ligand-induced IFN-γ production was diminished by APN while it had no influence on NK-cell cytotoxicity. In contrast only a small subpopulation of murine NK cells expresses surface AdipoRs, but about 90% store them intracellularly. APN-deficient knockout (KO) mice had elevated frequencies of NK cells. However, cytotoxic degranulation of NK cells was decreased in APN knockout (APN-KO) animals. Accordingly, frequencies of CD11b high CD27 high and CD94 high effector NK cells and expression of NKG2D were lower in APN-KO mice. Upon CVB3 infection NK-cell function was restored in APN-KO mice. Our data suggest that in addition to its antiinflammatory effects APN also influences the numerical and differentiation status of NK cells, which may further impact the outcome of immune-mediated diseases in APN-KO mice.Keywords: Adiponectin r Adiponectin KO mice r Adiponectin receptors 1 or 2 r Immunomodulation r NK cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAdiponectin (APN), a cytokine, accounting for 0.01% of total plasma protein, is mainly produced by adipocytes under steadystate conditions and negatively regulated by obesity [1,2]. Adiponectin has been shown to exert antiinflammatory effects in several disease models such as sepsis, inflammatory diseases, and Correspondence: Prof. Carmen Scheibenbogen e-mail: Carmen.Scheibenbogen@charite.de transplantation. In accordance, APN-deficient mice are more prone to transplant rejection and inflammatory diseases [3][4][5].APN signaling is mediated by two receptors, adiponectin receptor (AdipoR) 1 and 2, with different affinities for existing isoforms. AdipoR1 is ubiquitous, but most prominent in skeletal muscle and heart, whereas AdipoR2 is abundantly expressed in the liver [6]. AdipoRs expression was further described in cells of the immune system [7,8]. Several studies revealed the direct action of APN on cells of the innate and adaptive immune system [1,9]. APN was shown to inhibit TLR-mediated NF-κB activation in macrophageswww.eji-journal.eu Eur. J. Immunol. 2013. 43: 1024-1033 Immunomodulation 1025[10] and to induce macrophage polarization toward the antiinflammatory M2 phenotype [11]. In a recent study we could further demonstrate that T cells store AdipoRs intracellularly, upregulate them upon T-cell receptor activation, and that APN acts as a negative T-cell regulator for antigen-activated T cells [8]. Furthermore, APN has been described as a negative regulator of hematopoiesis inhibiting directly proliferation of myelomonocytic progenitors [12] or indirectly through inducing changes in stromal cells [13]. NK cells are innate effector lymphocyte...

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“…The NK-cell maturation status can be characterized by the expression of CD11b and CD27 [21,22]. CD11b low CD27 low defines immature and naive NK cells, whereas CD11b high CD27 high NK cells represent the most potent effector cells and the CD11b high CD27 low the terminally differentiated NK cells.…”

Section: Apn-ko Mice Show Diminished Nk-cell Degranulationmentioning

confidence: 99%

Adiponectin modulates NK‐cell function

et al. 2013

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“…While the CD11b high CD27 low population secreted lower levels of cytokines compared to the intermediate developmental stages, it was found that they still secreted more than the immature double negative subset. It was also concluded in this study that the immature double negative subset had the lowest cytolytic activity of the four subsets and that cytolytic activity increases with increasing NK cell development 9 . It makes sense therefore, that in our study we found the highest amounts of CD27 low CD11b low NK cells within pyMT tumors as these cells produce the lowest levels of IFN-c and TNF-a, are the least cytotoxic, and allow the tumor to continue to grow.…”

Section: Discussionmentioning

confidence: 84%

“…CD11b low CD27 low NK cells are the most immature subset displaying the highest rate of homeostatic proliferation and potential for differentiation. Although mouse and human NK cells do not necessarily share the same markers for identification, CD27 and CD11b can be used to identify distinct stages of NK cell development in both the human and mouse 9 . CD27 and CD11b double positive NK cells are considered mature and highly cytotoxic.…”

Section: Introductionmentioning

confidence: 99%

The breast tumor microenvironment alters the phenotype and function of natural killer cells

et al. 2015

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Natural killer (NK) cells are innate immune cells with the ability to identify and eliminate transformed cells. However, within tumors, many studies have described NK cells as non-functional. The developmental stage of tumor-associated NK cells and how this may relate to functionality has not been explored. We examined the developmental state of NK cells from polyoma middle T antigen (pyMT) transgenic mouse (MMTV-pMT) breast tumors. In pyMT tumors, NK cells were immature as evidenced by their decreased expression of DX5 and their CD27 low CD11b low phenotype. These immature NK cells also had increased expression of NKG2A and expressed low levels of NKp46, perforin, and granzyme B. In contrast, splenic NK cells isolated from the same mice maintained their maturity and their expression of activation markers. To delineate whether the tumor microenvironment directly alters NK cells, we adoptively transferred labeled NK cells and followed their activation status in both the spleen and the tumor. NK cells that arrived at the tumor had half the expression of NKp46 within three days of transfer in comparison to those which arrived at the spleen. In an effort to modify the tumor microenvironment and assess the plasticity of intratumoral NK cells, we treated pyMT tumors with IL-12 and anti-TGF-b. After one week of treatment, the maturity of tumor-associated NK cells was increased; thus, indicating that these cells possess the ability to mature and become activated. A better understanding of how NK cells are modified by the tumor microenvironment will help to develop strategies aimed at bolstering immune responses against tumors.

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“…Although NK cells are an important cell type within the innate immune system and also act as sentinel cells in other models (35-37), their exact function at the maternal-fetal interface remains incompletely defined. Recent studies have reported that CD27, which belongs to the TNF receptor family, is an important marker in distinguishing different subsets of NK cells (38,39). Based on the surface density of CD27 and CD11b, murine NK cells can be classified into four subsets that represent their different maturation stages (40).…”

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Natural killer cells promote immune tolerance by regulating inflammatory T_H17 cells at the human maternal–fetal interface

Sun

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells accumulate at the maternal-fetal interface in large numbers, but their exact roles in successful pregnancy remain poorly defined. Here, we provide evidence that T H 17 cells and local inflammation can occur at the maternal-fetal interface during natural allogenic pregnancies. We found that decidual NK cells promote immune tolerance and successful pregnancy by dampening inflammatory T H 17 cells via IFN-γ secreted by the CD56 bright CD27 + NK subset. This NK-cell-mediated regulatory response is lost in patients who experience recurrent spontaneous abortions, which results in a prominent T H 17 response and extensive local inflammation. This local inflammatory response further affects the regulatory function of NK cells, leading to the eventual loss of maternal-fetal tolerance. Thus, our data identify NK cells as key regulatory cells at the maternal-fetal interface by suppressing T H 17-mediated local inflammation.regulatory NK cells | fetomaternal tolerance D uring pregnancy, allogeneic fetal cells invade the maternal decidua but they are protected from the maternal immune system. This invasion of extraembryonic trophoblasts does not harm gestation during normal pregnancy; it establishes tolerance at the maternal-fetal interface (1), (2), although the mechanism of such tolerance is not clear. In addition, inflammatory responses induced by a variety of mechanisms can result in embryo loss, but mild inflammation can be effectively controlled through regulatory mechanisms to maintain successful pregnancy (3). Thus, suppression of strong inflammatory responses is essential to ensure normal pregnancy (4, 5), although the mechanisms involved in regulating local inflammation without compromising overall maternal immunity during a successful pregnancy remain unknown.Multiple mechanisms are potentially involved in promoting immune tolerance during pregnancy. For example, T H 2 cytokine polarization (6-9), the expression of the Fas ligand on trophoblast cells (10), and the inhibition of complement activation (11) are crucial for ensuring tolerance at the maternal-fetal interface. In addition, a delicate balance exists between inhibitory (PD-L1, Stat3, and TGF-β1) and stimulatory (CD80 and CD86) signals during the establishment of immune privilege (12-18). Furthermore, studies have shown that galectin-1 (19) and indoleamine 2,3-dioxygenase (20) play pivotal roles in maternal-fetal tolerance. Several types of immune cells, such as CD4 + CD25 + regulatory T cells, are also essential in the generation of maternal-fetal tolerance in mice and humans (7,(21)(22)(23)(24). Furthermore, natural killer (NK) T cells and immature dendritic cells have been reported to promote the expansion of Treg cells that confer protection of the fetus (19).Despite considerable progress, many questions remain unanswered. The most striking feature at the maternal-fetal interface is the accumulation of NK cells, which account for ∼60-90% of immune cells in the decidua in humans during early pregnancy (25)(26)(27)(28)(29) and a...

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CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells

Cited by 172 publications

References 41 publications

Adiponectin modulates NK‐cell function

Adiponectin modulates NK‐cell function

The breast tumor microenvironment alters the phenotype and function of natural killer cells

Natural killer cells promote immune tolerance by regulating inflammatory T_H17 cells at the human maternal–fetal interface

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CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells

Cited by 172 publications

References 41 publications

Adiponectin modulates NK‐cell function

Adiponectin modulates NK‐cell function

The breast tumor microenvironment alters the phenotype and function of natural killer cells

Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal–fetal interface

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Natural killer cells promote immune tolerance by regulating inflammatory T_H17 cells at the human maternal–fetal interface