NK cells have been the cells most extensively studied, primarily because they constitute the predominant
leukocyte population present in the endometrium at the time of implantation and in early pregnancy
In summary, in vivo animal experiments have shown an inhibitory role of estrogen on peripheral NK cell lytic activity, which is partly due to
suppression of NK cell output by the bone marrow and partly due to suppression of individual NK cell cytotoxicity. However,
in vitro studies so far have failed to show conclusively a direct effect of estrogen on NK cells.
At the progesterone
concentrations believed to be present in the uterus [up to 10−5 m at the maternal-fetal interface (35)], studies consistently show inhibition of lymphocyte proliferation (33) and inhibition of NK cytolytic activity in vitro
The exact role of prolactin in NK cell regulation is unknown.
The overall effects of estrogen on NK cells are likely multifactorial, therefore, and depend on the type of cell affected
as well as the kind of ER expressed by that cell.
It is known that progesterone can directly affect T cell differentiation in vitro, suppressing development of the Th1 pathway and enhancing differentiation along the Th2 pathway (44)
Th1 cells predominantly produce interferon-γ (IFN-γ), IL-2, and TNF-β and are involved in cell-mediated immunity. Th2 cells
produce IL-4, IL-5, IL-6, IL-10, and IL-13 and stimulate humoral immunity
Furthermore, in response to progesterone, γδ T cells produce progesterone-induced blocking factor (PIBF) (54
A defining characteristic of NK cells is their ability to lyse target cells without prior sensitization and without restriction
by HLA antigens.
NK cell function is mainly regulated by IL-2 and IFN-γ
IL-2 causes both NK cell proliferation and enhanced cytotoxicity.
IFN-γ augments NK cytolytic activity, but does not cause NK proliferation. The two cytokines act synergistically to augment
NK cytotoxicity (6).
The largest leukocyte population in the endometrium consists of NK cells named large granulated lymphocytes
there is a significant increase
in the number of uNK cells throughout the secretory phase, which peaks in early pregnancy when uNK cells comprise about 75%
of uterine leukocytes (62)
Second, uNK cell phenotype changes during the normal menstrual cycle and early pregnancy (68)
general proinflammatory effect of estrogen, causing an influx of macrophages and neutrophils, which is
antagonized by progesterone through its receptor (70, 71).
The mechanism of such a progesterone-induced local immunosuppression is unclear.
progesterone plays an important role in proliferation and differentiation of uNK cells (32).
Through promotion of a uterine Th2 environment, progesterone could indirectly affect uNK cell function
The mechanism of this increase in uNK cell numbers has been addressed
in both human and mouse models, and is likely the result of: 1) recruitment of peripheral NK cells to the uterus, and 2) proliferation
of existing uNK cells
prolactin system plays an important role in implantation and the maintenance of pregnancy
the exact pathways of hormonal regulation of NK cells remain to be delineated.
The exact function of uNK cells has not yet been unequivocally determined
uNK cells express a different cytokine profile, compared with resting peripheral NK cells. mRNAs for granulocyte
CSF, M-CSF, GM-CSF, TNF-α, IFN-γ, TGF-β, and leukemia inhibitory factor (LIF) have been found in decidual CD56+ cells
Their increased numbers in early pregnancy, their hormonal dependence, and their close proximity
to the infiltrating trophoblast all suggest that they play an important role in the regulation of the maternal immune response
to the fetal allograft and the control of trophoblast growth and invasion during human pregnancy
role of
uNK cell-derived cytokines on trophoblast growth and differentiation (114, 115, 116, 117).
Th1 immunity to trophoblast is associated with RPL, whereas Th2 immunity is associated
with a successful pregnancy
RPL is associated with Th1 immunity, for which NK cells are partly responsible.
long term BCAA supplementation (defined as > 6 months) shown to be safe and effective in liver cirrhosis malnutrition, liver failure and hepatic encephalopathy.
increased densities of T-cell infiltrates with a high proportion of CD8+ T cells within primary colorectal carcinomas were associated with a significant protection against tumor recurrence
coexpression of genes mediating cytotoxicity and TH1 adaptive immune responses accurately predicted survival in patients with colorectal carcinoma independently of the metastatic status.
Proinflammatory cytokines secreted by inflammatory cells can contribute to tumor progression, and soluble factors produced by the tumor in response to nonspecific or tumor-specific signals, such as prostaglandin E2 (PGE2), adenosine, or TGF-β, downregulate functions of immune cells
they are largely ineffective in arresting tumor growth, although they can proliferate and mediate antitumor cytotoxicity on their removal from the tumor bed and ex vivo IL-2 activation.42
DCs (HLA-DR+CD86+CD80+CD14−) are nature’s best APCs
They are a common component of tumor immune infiltrates and are responsible for the uptake, processing, and cross-presentation of TAs to naive or memory T cells, thus playing a crucial role in the generation of tumor-specific effector T cells
DCs control the induction of Treg cells. In patients with cancer, cellular interactions between antigen-presenting DCs and T cells lead to expansion and accumulation of Treg cells at the tumor site and in the periphery
NK cells (CD3−CD56+CD16+), which mediate innate immunity and contain both perforin-rich and granzyme-rich granules, are well equipped to mediate lysis of tumor cells
B cells (CD19+, CD20+) are also rare in most human tumors, with the exception of breast cancer and melanoma
The initial acute inflammation involving the recruitment and influx of antitumor effector cells is replaced by chronic inflammation in later stages of tumor progression
Tissue hypoxia plays a major role in shaping the nature of immune infiltrates in tumors
Another great review of the immune system during different stages of carcinogenesis; how the cancer manipulates the immue system to cloak itself from the immune system.