| Background and objectives:The immune system is a remarkably versatile defense system comprising innat immunity and adaptive immunity. These two elements are able to employ an enormous variety of cells and molecules acting together in a dynamic network to protect hosts from invading pathogenic microorganisms and cancers.An tigen -p resenting cells such as dendritic cells and macrophages, immune effector cells such as natural killer (NK) cells and cytotoxic T-lymphocytes(CTL),can recognize and kill or eliminate the invading pathogenic microorganisms and tumour cells though complex mechanisms. It is obvious that there are lots of immune defence responses against tumour cells in patients and tumor-bearing mice.simutaneously ,tumor induces immune tolerance to escape these immune attacks through secretion of cytokines and chemokines. Among which the generation and/or the expansion of inhibitory or regulatory cell populations (such as regulatory T cells, Treg) that negatively regulate immune cell functions have attracted much attention. 1995, Sakaguchi as the first will go apart from to discover CD4~+CD25~+ fraction of T cells transferred to nude mice will lead to a variety of autoimmune diseases, and at the same time the importation of CD4~+CD25~+T cells also can inhibit disease from happening. In the subsequent in vitro study also found CD4~+CD25~+T cells with a low response and immune suppression function, since the relevant CD4~+CD25~+regulatory T cells (regulatory T cells, Treg) of the study has been the rapid development.Immunosuppressive effects with Treg plays an important role in immune pathology, graft tolerance and suppress their own immune response and maintenance of immune balance. occurring naturally CD4~+CD25~+Treg in the body is from the thymus, the major surface markers are CD25, cytotoxic T lymphocyte antigen 4 (CTLA-4), IL-2 receptorβchain (CD122) and glucocorticoid-induced tumor necrosis factor receptor (glucocorticoid-induced TNF receptor, GITR). At the same time, CD4~+CD25~+ Treg cells with high expression of Foxp3 (transcription factor forkhead / winged helix family), which are the characteristic signs And CD4~+CD25~+Treg also express higher chemokine receptor, and the enzyme tryptophan (IDO), TGF-βand CD80 is a sign of their activation. At present, the group of CD4~+CD25~+ Treg cells can be divided into "natural" and "induced" categories. The "induced" CD4~+CD25~+ Treg cells, because of its difficult separation of research, the relationship with "natural CD4~+CD25~+Treg cells did not fully understand. Probably also because "induced" CD4~+CD25~+ Treg cells exist , the mechanism about CD4~+CD25~+ Treg multing become difficult. The "natural" CD4~+CD25~+ Treg cells, some scholars think that the groups are probably produced by the thymus as an independent group.But the challenging opinion on this hypothesis are: the groups are probably from periphery, only after the antigen stimulation it transfers back to the thymic medulla. Overseas evidence shows that two days after birth, the thymus has been contained with a CD4~+CD25~+Treg cell-like phenotype and function of cells, and at this time can not be detected in any type of T cells in the spleen . Early research also shows that at 3 days before birth, there is very little in peripheral CD4~+CD25~+Treg cells. However, the literature has reported that newborn rats bom to 3 days after thymectomy, CD4~+CD25~+ Treg cells and peripheral T cells decreased, but a significant quantity of the FOXP3 expression of CD4~+CD25~+ Treg cells can be detected . Based on the above results, we think: at least party "natural" CD4~+CD25~+ Treg cells are from the thymus.Early reports, CD4~+CD25~+ Treg cells showed the incompetence of the immune. But recently, including Earle, some different research groups, under different conditions made the cell proliferating. Earle, separation from human peripheral blood CD4~+CD25~+ Treg cells in vitro with anti-CD3 and anti-CD28 antibody covalently linked to the super-paramagnetic beads and a high concentration of exogenous IL-2 stimulation can be amplified 200 times. Moreover, the amplified cells remains with high CD25, CD62L, HLA-DR, CCR6, and FOXP3 expression, such as Treg cells with molecular markers in anti-CD3 or antigen stimulation of the same species can inhibit the effect of PBMCs proliferation and cytokine secretion . so CD4~+CD25~+ Treg cells are not immune incompetence, but its conditions of proliferation is different with traditions T cells. CD4~+CD25~+ Treg cells in the immune regulation function has been positived, there is a large number of experiments to prove that the cells on the immune tolerance play an important role in both self and non-self.CD4~+CD25~+Treg have two obvious immunological characteristics. First, immune incompetence,whch did not respond to the stimulation with high concentrations of interleukin-2 (IL-2) alone or to stimulate T-cell receptor (T cell receptor, TCR), also no secretion of IL-2; but in vivo we found that antigen-specific Treg has significant proliferative activity, but also highly dependent on the existence of specific antigen. Secondly: immunosuppressive It performances to inhibit the activation and proliferation in the TCR-mediated activation signals to stimulate their own after the T cells, but in the body exert its immunomodulatory function, and the mechanism to maintain their own detailed immune tolerance are not clear. Sakaguchi consider the role of such mechanisms are possible through direct contact with the way cells to play the role, or through secretion of regulatory cytokines such as interleukin-10 (IL-10), TGF-βand by inhibiting the maturation of dendritic cells, etc. way to play the role. Some Reported that FoxP3 over-expression at CD4~+ T naive cells are the main reasons of CD4~+CD25~+Treg with low response and inhibition. Many studies have found that, in gastric cancer, esophageal cancer, liver cancer, pancreatic cancer, breast cancer, nasopharyngeal carcinoma patients with different malignant tumors in peripheral blood, lymph nodes and tumor infiltration of regional organizations, there are CD4~+CD25~+ Treg ratio increased situation, and there was a significant correlation with the higher the level of progress with the course of disease and clinical pathology. Is still a lack of clear evidence to confirm the mechanisms of body tumor CD4~+CD25~+Treg how to mult. However, the possibility that there is the following:①tumor secreted some factor which directly or indirectly to attractand induce CD4~+CD25~+ Treg specific amplification. Curiel study found that patients with ovarian cancer tumor cells secreted chemokine CCL22, which recruit CD4~+CD25~+ Treg to the tumor site, resulting in CD4 + CD25 + Treg accumulation in tumor tissues of the situation, and in the normal Ovarian tissue can hardly see the CD4~+CD25~+Treg.②antigen-presenting cells presenting the tumor-associated antige can induce the expansion of Treg.③the body induced by the tumor continued to stimulate the formation of inflammation as a physiological defense situation.④At the clone-specific antigen for the delete or Fas-FasL-mediated apoptosis, CD4~+CD25~+Treg and CD4~+CD25~- Treg are different in sensitivity, secretion of tumor factor may be selective induced CD4 + CD25~- Treg apoptosis. At present, there is no report about the expression of CD4~+CD25~+Foxp3~+ Treg cells in peripheral blood of lung cancer, lung cancer and adjacent cancer tissues and the multing mechanisms. Our study is to observe the phenomenon of CD4~+CD25~+Foxp3~+ Treg cells in lung cancer patients with abnormal aggregation, and further explore its mechanism and regulation in patients with lung cancer in vivo immunosuppressive effects.Methods:The percentage of the CD4~+CD25~+Foxp3 + regulatory T cells in the tumor tissues,in the normal tissues and peripheral blood from 45 patients with NSCLC and 15 healthy controls was detected by flow cytometry. The cell morphology was observed by fluorescence microscopy . carry out one way analysis of variance to the data by SPSS13.0 statistics software and compare two value of each group.Results:The proportion of CD4~+CD25~+Foxp3~+ regulatory T cells in CD4~+ T cells is 10.54±1.12% in the tumor tissues; the percent of CD4~+CD25~+Foxp3~+ regulatory T lymphocytes in peripheral blood and the normal tissues are 8.24±2.16% and 3.62± 1.24% in the 45 Patients with lung cancer. The percent of CD4~+CD25~+Foxp3~+ regulatory T lymphocytes in the tumor tissues is significantly higher than that of peripheral blood and adjacent tissues (p<0.05),and the percent of the CD4~+CD25~+Foxp3~+ regulatory T lymphocytes in the Peripheral blood of patients with lung cancer (9.28±2.10%) was significantly higher than that of volunteers (2.63±1.28%). Combined with clinical data analysis ,it showed that the percent of CD4~+CD25~+Foxp3~+ regulatory T cells in lung adenocarcinoma (11.26±3.12%) is higher than that of squamous cell carcinoma (8.34±2.90%) , and it has a certain relevance with the clinical stage of tumor.And the high expression of Treg has a certain relevance with the clinical stage of tumor. it showed that the percent of CD4~+CD25~+Foxp3~+ regulatory T cells in the peripheral blood of III,IV stage is higher than that of I,II stage.Conclusion:CD4~+CD25~+Foxp3~+ regulatory T cells in the peripheral blood and lung cancer is high-expression and promote the further deterioration of the tumors .In different tissue typing of cancer there are significant differences, the Expression of Treg in lung adenocarcinoma is higher than that of squamous cell carcinoma, this may be a new target for immunotherapy. The high expression of Treg has a certain relevance with the clinical stage of tumor, it also can be used for lung cancer diagnosis and prognosis as the detection of recurrence and, as well as a target to observe immune therapy. |
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