CD4 CD25 regulatory T cells and head and neck cancer
Abstract studies have found a unique regulatory function of immune T-cell subsets CD4 CD25 regulatory T cells in autoimmune balance play an important role, not only can inhibit autoimmune disease, but also may be involved in tumor immune escape process. Head and neck cancer are known in the local environment, there are many immunosuppressive factors such as TGF β, VEGF, COX 2 and so on, they are in the
process of tumor immune escape to play an important role. This paper will CD4 CD25 regulatory T cells and the interaction of
the above-mentioned immunosuppressive factor to make a review to explore the CD4 CD25 regulatory T cells in head and neck cancer in the role of local immune suppression.
Key words Head and neck tumor immune suppressor CD4 CD25 regulatory T cells
A1 CD4 CD25 regulatory T cells
Sakaguchi et al  first reported the CD4 CD25 regulatory T (Treg) cells in the regulation of T-cell subsets,
one originated in the thymus, followed by peripheral immune organs can continue to produce. With low response and immune suppression of two main characteristics: the low reactivity refers to amplification and propagation in vitro is difficult; immune suppression refers to CD4 CD25 regulatory T cells can inhibit CD4 and CD8 T-cell activation and proliferation;
inhibition with the cell surface CTLA 4 and GITR expression
is closely related to [2 4]. Its main function is to
inhibit self-antigens or foreign antigens on the abnormal immune response, activated after the secretion of a large
number of IL 10 and TGF β, inhibit Th1-mediated
immunity and inflammation, Th2-mediated antibody production
and CD8 CTL activity . Foxp3 specifically expressed in CD4 CD25 Treg cells, and in the maintenance of cell development and function play a very important role in CD4 CD25 Treg cells is a characteristic sign .
CD4 CD25 Treg cells in the body's immune appearance emerged in a strong inhibitory effect on experimental animal models of autoimmune disease, reduce the incidence of infusion of such cells, while the removal of such cells can induce autoimmune diseases [1,6], showed that CD4 CD25 Treg cells in maintaining self-tolerance play an important role. CD4 CD25 Treg cells can inhibit T-cell antigen of external sources and its own immune response, and therefore the maintenance of
immune tolerance to their own constituents but also may prevent the body's response to autologous tumor cells immunization. In cancer patients, many from the autologous T cell recognition of tumor-associated antigen has been proved
to be normal since the body composition, rather than the product of the abnormal gene mutation, indicating that tumor immunity to a certain extent, is also an autoimmune. In ovarian cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer and other cancer patients and tumor localized in peripheral blood CD4 CD25 Treg cell components to increase , suggesting that cancer patients may have a natural immune response, and has the promotion of local The role of immunosuppression. Because CD4 CD25 Treg cells in the presence of CD8 T cells in local tumor showed active though, but the expression of IL 2Rα was suppressed to make it to the
stimulation of IL 2 no response, it can not effectively
kill tumor cells . This illustrates the CD4 CD25 Treg cells
in the tumor play an important role in immune suppression. Xia et al  The study found, CD4 CD25 Treg cells in the peripheral blood of patients with laryngeal carcinoma in a substantial increase, with secretion of TGF β, IL 10
capacity, down T cell-mediated tumor immunity; another study  found in patients with nasopharyngeal carcinoma in peripheral blood CD4 CD25 Treg cells was significantly higher than the normal control group, given the CD4 CD25 Treg cells in patients with nasopharyngeal carcinoma may be an important reason for the immune suppression, so CD4 CD25 Treg cells in head and neck tumor immune suppression to play a an important role.
Two local immunosuppressive factor on tumor CD4 CD25 Treg
cells in regulation
Head and neck cancer cells can spontaneously secrete immunosuppressive cytokines, such as TGF β, COX 2 and
downstream products of PGE2, vascular endothelial growth factor (VEGF) and so on, can inhibit T cell differentiation, promoting Th1/Th2 balance towards Th2 shift , and down T-cell
adhesion or (and) the expression of costimulatory molecules to induce tumor-specific CTL tolerance, its mechanisms are different. With the CD4 CD25 Treg cell research, in-depth, can
be found in the above-mentioned factors on the different ways
of tumor Treg cells regulate in vivo.
3 TGF β on the regulation of CD4 CD25 Treg cells
Almost all epithelial origin of head and neck tumor and tumor cell lines may secrete abnormal amount of transforming growth factor (transforming growth factor, TGF) β1, β2. TGF
β-mediated tumor immune escape is the most effective immunosuppressive molecules through autocrine / paracrine way to inhibit a variety of immune cells in the tumor tissue infiltration; inhibit tumor cell surface target sub-segments
(such as: HLA DR) , B7 1, intercellular adhesion
molecule-low or even no expression ; inhibit various immune cell proliferation, differentiation, activation, and by down-regulating Bcl 2 mRNA expression induced apoptosis in
activated immune cells; inhibit Th1-type and inflammatory
cytokine production and activity, promoting Th2 shift; closure initiated by the cytokine signal transduction pathways; inhibit CTL, NK cells, CD3, FCR ? molecule ζ chain and
cytoplasmic protein tyrosine, serine, threonine
phosphorylation, hinder the immune activity of cells in the activation of transcription factors, leading to perforation of protein synthesis blocked granzyme B; enhanced CD94 / N KG
A in T, NK cells, significantly down-activated receptor NKp30,
NKG D of the expression, affect the T, NK cell activation and inhibitory signals in balance; inhibit the secretion of immunoglobulin IgG, reducing B cell IgM, IgG expression, thereby suppressing humoral immunity; directly or indirectly
promote tumor cell growth, etc. [12 , 13].
TGF β and CD4 CD25 Treg cells in head and neck tumor immune suppression mutually reinforcing roles to play: First, CD4 CD25 Treg cell activation and subsequent secretion of a
large number of TGF β, inhibit Th1-mediated immunity and
inflammation, Th2-mediated antibody production as well as CD8 CTL activity, involved in promoting tumor immune dysfunction. Second, the in vivo experiments show that TGF β on the
inhibition of CD4 CD25 T cells are essential . There are
experimental results show that, TGF β not only as a
soluble cytokine, but also expressed in activated CD4 CD25 T cell surface, which means you can contact the cell membrane interactions . Recent studies have shown that, TGF β-
induced Foxp3 expression to play an important role. TCR stimulation and the combined effects of TGF β can induce
Foxp3 in CD4 CD25-T cells, these cells into a Treg cell
activity in CD4 CD25 T cells [16,17]. Similarly, in vivo, TGF
β signal transduction pathway may also generate Treg
cells, because transient expression of islet TGF β, can
induce expression of Foxp3 in Treg cell generation . And, TGF β can induce skin graft tolerance, while inducing the expression of Foxp3 . In addition, CD4 CD25 Treg cells by
infecting immune tolerance mechanisms, discipline CD4 CD25-T
cells into a regulating activity of CD4 CD25 T cells, may also be induced by TGF β expression of Foxp3 achieved . The experiments reveal that, TGF β through certain channels,
regulation of the expression of Foxp3 in CD4 CD25 Treg cells play a role in the formation.
4 VEGF on the regulation of CD4 CD25 Treg cells,
Vascular endothelial growth factor (VEGF), by the majority of head and neck cancer cells and cell strains,
including thyroid cancer, tongue cancer, also by tumor stromal cells and infiltration of Mφ release. As autocrine /
paracrine molecule, VEGF may affect dendritic cell (DC) differentiation and mature, and to inhibit antigen-presenting
function, further affect the expansion of CTL, activation and tumor cell sensitivity to CTL destruction; by upregulating the Bcl 2 expression inhibits tumor cell apoptosis; as fibroblasts and vascular endothelial cells implanted to provide matrix support material to promote formation of blood
vessels and enhance blood vessel formation NRP 1
(Neuropilin 1) mechanism, eventually leading to
neovascularization a large number of formation . VEGF can be directly or indirectly enhance the CD4 CD25 Treg cells in
immune function, thereby inhibiting the body involved in tumor immunity: reposted elsewhere in the paper for free Download
VEGF on the one hand by inhibiting nuclear factor κB
(NF κB) transcriptional activity, impede, DC
differentiation and maturation, indirect-induced CD4 CD25 Treg
cells were increased and its activity was enhanced, thereby suppressing the body's immune response to tumors. Studies have found that VEGF can inhibit TNF α receptor pathway of IKK-
catalyzed phosphorylation of IκB, thereby reducing NF κB
transcriptional activity and inhibit dendritic cell (DC) differentiation, manifested in the body of mature dendritic cells ( mDC) reduction, local immature cells (iDC) increase in . The iDC can induce CD4 CD25 Treg cells , because
with allogeneic immature dendritic cells to stimulate resting repeated cord blood T cells can produce a group of low-growth
capability and can produce T-cells, IL 10 , and their
inhibition with CD25 T cells in a similar, including contact-
dependent, antigen non-specific. Further study, this
inhibitory effect was partially offset by added IL 2.
On the other hand, VEGF by inhibiting nuclear factor
κB (NF κB) transcriptional activity of CD4 CD25 Treg cells to enhance immune function, thereby inhibiting the
body's immune tumor. Tumor necrosis factor superfamily member GITR have been proven to regulate CD4 CD25 Treg cell function, GITR antagonist antibodies can block the CD4 CD25 Treg cell-
mediated tumor immune suppression, but the CD4 CD25-T cells
has no effect [24, 25], suggesting that the body there is GITR ligand (GITRL), can block the CD4 CD25 Treg cells with immunosuppressive function. Such speculation was subsequently confirmed and found that the blocking function and CD4 CD25 Treg cells, NF κB activation , CD4 CD25 Treg cells, NF
κB activation can block the effect of this increase. VEGF can inhibit TNF α receptor pathway of IKK-catalyzed
phosphorylation of IκB, thereby reducing NF κB
transcriptional activity, so that GITRL on CD4 CD25 Treg cells
in immune suppression to reduce the blocking effect, namely, the relative increase CD4 CD25 Treg cells in immune function, thereby inhibiting the body's immune tumor.
5 COX 2 and its downstream products of PGE2 on the
regulation of CD4 CD25 Treg cells in
Cyclooxygenase 2 (cyclooxygenase 2, COX 2) in a
number of head and neck tumor tissues overexpressed, but also metastasis in the lymph nodes and other organizations around the tumor angiogenesis in the over-expression. COX 2 could
inhibit neutrophil infiltration and Mφ activation; promote M
φ, lymphocytes produce IL 10, blocking Mφ produce IL
12, thus inhibiting IL 12 Dui Th1-type immune response
induced; inhibit TNF, IL 1 generation, resulting in
decreased cellular immune function; catalytic activity of expendable substrate regulation of arachidonic acid to activate caspase 3, changes in mitochondrial permeability and induce apoptosis of immune cells; so free of arachidonic acid reduced, and thus inhibit tumor cell apoptosis; by promoting prostaglandins (prostaglandin, PG) produced an increase, induced high Bcl 2 expression and low expression of TβR
?, reduce transmembrane N ceramide acid concentration, so
that tumor cell growth, apoptosis , the formation of new blood
vessels to change, thereby increasing the potential for tumor metastasis, inhibit immune surveillance; through the EP2 receptor in cell surface signal transduction and increased VEGF, PGE2, endothelin, matrix metalloproteinase (mat rix
metalloproteinase, MMPs) such as tumor angiogenesis factor expression, stimulate Bcl 2 or Akt activation to inhibition
of vascular endothelial cell apoptosis, increases vascular permeability and blood flow in blood vessels has been formed to promote CD44 (tumor cell surface hyaluronate receptor) over-expression of induced tumor angiogenesis [27 29].
The recently Sharma et al  study found that, COX 2
and its product PGE2 can induce Foxp3 in CD4 CD25 Treg cells, increasing CD4 CD25 Treg cell activity, and PGE2 can also
induce Foxp3 in CD4 CD25-T cells the expression of these cells into a Treg cell activity in CD4 CD25 Treg cells, increasing the number of CD4 CD25 Treg cells. Animal studies COX 2
inhibitors can reduce the number of CD4 CD25 Treg cells,
reducing its activity to reduce the tumor-infiltrating Foxp3
in the lymphoid tissues, reduce tumor burden; to CD4 CD25 Treg cells or PGE2 moved to accept the COX 2 inhibitors in mice,
you can reverse the role, but moved into CD4 CD25-T cells and
not affect the tumor growth rate. This illustrates the COX
2/PGE2 can enhance the CD4 CD25 Treg cell immunosuppressive activity, promote tumor immune tolerance.
To sum up, in the head and neck tumors, the immune inhibitory factor TGF β, VEGF, COX 2 expression in CD4
CD25 Treg cells can enhance tumor immune inhibition, therefore, if we can specifically inhibit the function of CD4 CD25 Treg cells , you can block TGF β, VEGF, COX 2 on
tumor immune escape mediated by effectively induce tumor
immune response, to achieve therapeutic goals. Because CD4 CD25 Treg cells and other T-cell surface molecules on the
surface of the differences have not yet entirely clear, in the human body to remove CD4 CD25 Treg cells in inducing tumor immunity, while autoimmune diseases may occur, so further study of the characteristics and functions of such cells to clarify how it can inhibit the body's autologous tumor cells attack, contribute to a better understanding of tumor immune tolerance mechanisms and access to effective cancer treatment.
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