The Mechanism And Role Of CD4+CD25+Treg Cells In Tumor Immune Tolerance

One function of the immune system immune surveillance in the removal of tumor cells plays an important role.When the body's normal cells mutate into tumor cells,the immune system can produce a series of immune response to eliminate tumor cells.However,because of the rising incidence of clinical tumor,immune surveillance function of the existence,effect and impact of new factors have started to look at.Tumor cells can induce some mechanism of tolerance to evade immune surveillance and in the body growth and metastasis.It is hoped that from the tumor "immune escape" mechanisms revealed that tumor cells effective to prevent the "immune escape",to reduce the incidence of cancer and development.Therefore,the tumor's "immune escape" mechanism has been the focus of attention intumor immunology.one of the mechanisms of tumor "immune escape" are probably tumor cell-induced autoimmune tolerance. But is still not clear what the mechanism involved in tumor immune tolerance of the "immune escape."Since 1995,Sakaguchi et al first proposed CD4+CD25+regulatory T cells(Regulatory T cells,Treg),immunization academics more and more aroused the concem of many,has carried out extensive research.CD4+CD25+Treg cells are unique Lymphocyte subsets and naturally occurring in thymus,CD4+T cells accounted for 5%-10%.CD4+CD25+Treg cells in the TCR library to identify their own and foreign antigens,but with priority to identify the characteristics of autoantigen.Activated CD4+CD25+Treg cells not only inhibit efficient CD4+and CD8+effector T cell proliferation and cytokine secretion capacity,also can effectively inhibit NK cells,B cells and DC cell function.It can be through cell contact-dependent mechanisms or inhibition of cytokine-dependent mechanism of inhibiting its own Self-reactive T cell activation and maintain self-immune tolerance and prevent the occurrence of autoimmune disease.Tumor antigens are self antigens quantity or a qualitative change,,therefore,it can be speculated CD4+CD25+Treg cells in maintaining self-tolerance, but also can inhibit the occurrence of tumor immunity.Study found that cancer patients or tumor animal model,CD4+CD25+Treg cell number and function are increased to varying degrees in peripheral,to remove CD4+CD25+Treg cells,the body can promote the response to tumor cell antigen in order to benefit a wide range of tumor antigen-induced immune response.Thus,CD4+CD25+Treg cells may play an important role at tumor escape and growth of the tumor,or it may be the reason that immunoenhancer and tumor vaccine will not be effective.TLRs is a class of receptors that can identify the structure of the highly conserved motif on pathogenic microorganisms-pathogen associated molecular patterns,mainly expressed in immune cells,especially macrophages and dendritic cell surface,to play an important role at the body's natural immune and acquired immune.To date,11 kinds of human TLRs and 13 mouse TLRs have discovered.TLRs in antigen-presenting cells such as DCs regulate acquired immune responses,play an important role in the process,the activation of different,TLRs can induce T cells into Thl,Th2 or regulatory T cell in different directions and so on.Research has found that TLR9 may be by inhibiting the maturation of DC and induction of regulatory T cells,to play the role of induced tolerance.Our group previous research also confirmed TLR9 expression on APC,can direct impact on CD4+CD25+Treg cell generation and function. Therefore TLRs and CD4+CD25+Treg cells have a very close relationship.Recently,people study TLRs on the immune system,found that tumor cells can express a variety of TLRs,the significance of the phenomenon that the tumor cells express TLRs in tumor immune tolerance, especially the relationship between tumor cell surface expression of TLRs and immune escape of tumor cells,causing the interest of many researchers,but the expression of TLRs in tumor cells at the tumor occurrence and development of the role is not yet clear,to be further studied. Therefore,we speculate at tumor cell surface expression of TLRs with the role of TLRs on APC similar,through the regulator to influence some of CD4+CD25+Treg cell function,helping tumor to escape immune surveillance.Therefore,the CD4+CD25+Treg cells and tumor immunity,we asked the following question:1.CD4+CD25+Treg cells can inhibit tumor-reactive T cell activation,involved in tumor immune tolerance,thereby promoting tumor "immune escape"?2.If the CD4+CD25+Treg cells involved in tumor immune tolerance,the induction of tolerance and the mechanism is related to the expression of certain TLRs?Therefore in order to clarify the CD4+CD25+Treg cells and tumor occurrence and development of the relationship and significance,The purpose of this study was to explore CD4+CD25+Treg cells changes and effect of tumor cell to CD4+CD25+Treg,from the following three areas: 1.Study of lung cancer,breast cancer patients and tumor animal model of CD4+ CD25+ Treg cell number and functional changes First of all study patients and tumor animal model of tumor CD4+CD25+Treg cell number and function of changes,clear CD4+CD25+Treg cells is associated with the occurrence of tumor.To lung cancer,breast cancer,Lewis lung cancer in mice and S180 ascites carcinoma in mice as the research object,We Observed CD4+CD25+ Treg in the tumor patients and animal models of tumor number and function changes,The study found:Lung cancer,breast cancer patients peripheral blood CD4+CD25+Treg cell increased in number and function;Lewis lung cancer mouse spleen CD4+CD25+Treg cell increased in number and function,accompanied by T cell proliferation and killing functionality; S180 ascites carcinoma mice in TIL CD4+CD25+Treg cell increased in number and function, accompanied by CD8+T cell function decline.Prompted CD4+CD25+Treg cells may inhibit the immune response against the tumor cells,thus helping tumor to escape immune destruction.2.Study the effect of Lewis lung cancer cell and lymphocyte co-culture to Treg cells number and function Through research studies the impact of Lewis lung cancer cell and lymphocyte co-culture to Treg cells,explore in the tumor immune microenvironment tumor cells in local immune cells interactions on impact of CD4+CD25+Treg cells function.To us with the mouse Lewis lung cancer cells co-cultured lymphocytes were studied to observe that the Lewis lung cancer cells affect CD4+CD25+Treg cells.The study found:Lewis lung cancer cells and mouse lymphocytes after co-cultured CD4+CD25+Treg cells increase in number and function;Lewis lung cancer cells supernatant can induce CD4+CD25+Treg cells that increased in number and function.Prompting tumor cells can induce CD4+CD25+Treg cells,are probably escape tumor immune surveillance mechanisms.3.Possible mechanisms of TLRs on Lewis lung cancer cells affecting Treg cells number and function In order to explore Tumor cells effect on CD4+CD25+Treg cells,we detected the Lewis lung cancer cells and lymphocytes after co-cultured Lewis lung cancer cells changes in the expression of TLRs,and to further study whether the tumor cells through TLRs affect the CD4+CD25+Treg cells,thus contributing to tumor escape.Study results showed that Lewis lung cancer cells and lymphocytes after co-culture can affect the expression of multiple TLRs, including TLR4,5,9 upregulation;blocking TLR9 can reduce CD4+CD25+Treg cell number and function,but TGF-βhad no significant impact,TLR9 probably through other mechanisms affect CD4+CD25+Treg cells.The results showed that the tumor cells through TLRs possible impact of CD4+CD25+Treg cells involved in tumor immune escape,tumor-induced immune tolerance and promote tumor occurrence and development. Comprehensive study on,we come to the following conclusions:1.Cancer patients and tumor animal model of CD4+CD25+Treg cells increase in the number and function,accompanied by decreased immune surveillance function;2.Lewis lung cancer cells and their supernatants could induce CD4+CD25+Treg cells increase in the number and function.Tumor cells can induce CD4+CD25+Treg cells,are probably escape tumor immune surveillance mechanism;3.Lewis lung cancer cells through TLR9 to promote CD4+CD25+Treg cells increase in the number of enhancements to participate in the tumor-induced immune tolerance,thus contributing to the occurrence and development of tumor.This study explored the tumor cells to CD4+CD25+Treg cells and may be involved in mechanisms for a comprehensive understanding of tumor immune escape mechanism to provide new experimental evidence,and for CD4+CD25+Treg cells for tumor immunotherapy targets provide a new way of thinking.