Effects Of The Immunological Molecules On Type I Diabetes And Tumors

The immunological molecules,including cytokines and cell surface molecules, are indispensable members of immune system and play important roles in immune responses.They are constantly in the spotlight of immunology studies. Immunological molecules as well as their relevant immune cells participate extensively in normal immunological and physiological functions and abnormal immune responses(e.g.,autoimmune reactions) and tumorigenesis processes.In this study,more will be focused on the effects of interleukin-15(IL-15) and CD47,a membrane surface molecule,along with their associated immune cells,on the autoimmune typeâ… diabetes and tumor genesis in the whole immune system.1.Typeâ… diabetes(T1D) is an autoimmune disease characterized by infiltration of multiple inflammatory cells(mainly T cells),causing insulitis and immune destruction of the insulin-producingβcells of the pancreatic islets,leading to insulin deficiency,and hyperglycemia.The non-obese diabetic(NOD) mouse is a classical model of spontaneous autoimmune disease resembling human T1D.The autoimmune process in the pancreas of NOD mice includes two major checkpoints,which control the onset of insulitis and the switch to overt diabetes,respectively.The immune system in NOD mice harbors serious defects in multiple subsets of leukocytes including reduced NK cell activity,defects in NKT cells,and deficiencies in regulatory CD4⁺CD25⁺ T cells(Treg).NK cells and Tregs play important roles in the development of T1D.As a key NK cell agonist,IL-15 plays an essential role in NK cell development,survival,and function.This cytokine also improves the survival and function of T cells,including Tregs.IL-15,NK cells and Tregs interact together with one another;influence the pathogenesis of T1D in NOD mice.In the present study,we show that repeated injections of rmIL-15 mediate significant protection against T1D development in NK cell-depleted,but not NK cell-competent,NOD mice.IL-15 treatment stimulates Treg function both in vitro and in vivo,and this activity is,at least,one of the important mechanisms mediating its protective effect in NOD mice. Our data also demonstrate that IL-15 augments the regulatory function of CD4⁺CD25⁺ T cells by upregulating Foxp3 expression.Furthermore,IL-15-activated NK cells in vitro can abrogate the effect of IL-15 on Foxp3 expression in Tregs via IFN-γ, production,leading to attenuation of enhanced function of Tregs to some extent.2.CD47,is a highly glycosylated membrane surface self-antigen,interacts with extracellular matrix proteins and ligands to regulate immune system.CD47 modulates a series of tissues and cells functions,and has the ability to distinguish "self"from "non-self".CD47-SIRPαreceptor pair interaction reciprocally blocks CD47^+/+ cells phagocytosis by scavengers,and plays key roles in the immuno-regulatory functions of bone marrow transplantation and xeno-transplantation.Furthermore,CD47 is one of the co-stimulatory receptors of T cells,will help and enhance TCR signal transduction.Notably,CD47 can also mediate apoptosis of activated T cell.CD47 monoclonal antibody and its ligand TSP-1 can induce CD47-mediated apoptosis pathway.Some tumor cells(e.g.,T lymphoma EL4 cells) express CD47 and block phagocytosis of phagocytes in order to escape from the surveillance of immune system.Interestingly,some other tumors(e.g.,Jurkat cells) do not express or express less CD47,which may be linked to its induction of cell self-apoptosis.In this study, we show that T lymphoma EL4 cells express CD47 molecules.After treating the EL4 cells in vitro with RNAi and overexpression of exogenous protein techniques,we have obtained EL4 clones with distinct expression levels of CD47 molecules on the cell surface(CD47^lowEL4 and CD47^high EL4).When inoculated these EL4 clones into C57BL/6 mice,we find that the mice with CD47^low EL4 come to die earlier than control mice;while those with CD47^high EL4 appear the trend of delaying the time phase of death.Notably,many tumor cells from the livers of mice with CD47^low EL4 reverse to express normal level of CD47 molecules.These phenomena indicate that CD47^low EL4 may enhance its ability to anti-apoptosis owing to the low levels of CD47 expression,and prolong the time-phase of tumor cells self-renewal,leading to the augmented metastasis of tumors.In contrast,CD47^high EL4,having an increasing ability to induce apoptosis pathway due to the overexpression of CD47 on the surface, can accelerate the self-apoptotic process of EL4 tumors,delaying the death phase of the mice with CD47^high EL4 consequentially.