CD4^(+)CD25^(+) T regulatory(Treg)cells are critical in inducing and maintaining immunological self-tolerance as well as transplant tolerance.The effect of low doses of whole-body irradiation(WBI)on CD41CD251Foxp31 Treg cells has not been determined.The proportion,phenotypes and function of CD4^(+)CD25^(+) Treg cells were investigated 0.5,5 and 15 days after euthymic,thymectomized or allogeneic bone marrow transplanted C57BL/6 mice received 2-Gy c-rays of WBI.The 2-Gy WBI significantly enhanced the ratios of CD41CD251 Treg cells and CD4^(+)CD25^(+)Foxp3^(+) Treg cells to CD41 T cells in peripheral blood,lymph nodes,spleens and thymi of mice.The CD41CD251 Treg cells of the WBI-treated mice showed immunosuppressive activities on the immune response of CD4^(+)CD25^(+) T effector cells to alloantigens or mitogens as efficiently as the control mice.Furthermore,2-Gy c-ray WBI significantly increased the percentage of CD4^(+)CD25^(+)Foxp3^(+) Treg cells in the periphery of either thymectomized mice or allogeneic bone marrow transplanted mice.The in vitro assay showed that ionizing irradiation induced less cell death in CD4^(+)CD25^(+)Foxp3^(+) Treg cells than in CD4^(+)CD25^(+) T cells.Thus,a low dose of WBI could significantly enhance the level of functional CD41CD251Foxp31 Treg cells in the periphery of naive or immunized mice.The enhanced proportion of CD41CD251Foxp31 Treg cells in the periphery by a low dose of WBI may make hosts more susceptible to immune tolerance induction.
Complications arising from abnormal immune responses are the major causes of mortality and morbidity in diabetic patients.CD4^(+)CD25^(+)T regulatory cells(Tregs)play pivotal roles in controlling immune homeostasis,immunity and tolerance.The effect of hyperglycemia on CD4^(+)CD25^(+)Tregs has not yet been addressed.Here we used streptozotocin(STZ)-induced diabetic mice to study the effects of long-term hyperglycemia on CD4^(+)CD25^(+)Tregs in vivo.Four months after the onset of diabetes,the frequency of CD4^(+)CD25^(+)Foxp3^(+)T regulatory cells was significantly elevated in the spleen,peripheral blood lymphocytes(PBLs),peripheral lymph nodes(pLNs)and mesenteric LNs(mLNs).CD4^(+)CD25^(+)Tregs obtained from mice with diabetes displayed defective immunosuppressive functions and an activated/memory phenotype.Insulin administration rescued these changes in the CD4^(+)CD25^(+)Tregs of diabetic mice.The percentage of thymic CD4^(+)CD25^(+)naturally occurring Tregs(nTregs)and peripheral CD41Helios1Foxp31 nTregs were markedly enhanced in diabetic mice,indicating that thymic output contributed to the increased frequency of peripheral CD4^(+)CD25^(+)Tregs in diabetic mice.In an in vitro assay in which Tregs were induced fromCD4^(+)CD25^(+)T cells by transforming growth factor(TGF)-b,high glucose enhanced the efficiency of CD4^(+)CD25^(+)Foxp3^(+)T inducible Tregs(iTregs)induction.In addition,CD4^(+)CD25^(+)T cells from diabetic mice were more susceptible to CD4^(+)CD25^(+)Foxp3^(+)TiTreg differentiation than those cells from control mice.These data,together with the enhanced frequency of CD4^(+)CD25^(+)Foxp3^(+)T iTregs in the periphery of mice with diabetes,indicate that enhanced CD4^(+)CD25^(+)Foxp3^(+)T iTreg induction also contributes to a peripheral increase in CD4^(+)CD25^(+)Tregs in diabetic mice.Our data show that hyperglycemia may alter the frequency of CD4^(+)CD25^(+)Foxp3^(+)T Tregs in mice,which may result in late-state immune dysfunction in patients with diabetes.
The diversity of alloreactive T cells in graft rejection and the presence of extensive crossreactivity among alloreactive T cells indicate thatthe induction oftransplantation tolerancemay fundamentally alter the size ofhost T-cell repertoireinvolved in protective immunity and immune surveillance,especially those that are crossreactive to conventional antigens.We herein highlight the crossreactive nature of alloreactive T cells and the potential risks of altered T-cell repertoire associated with the induction of transplantation tolerance.The possibility that T-cell tolerance to one set of antigens results in their tolerance to other unrelated antigens due to T-cell crossreactivity and/or heterogeneity is defined as‘cross-immune tolerance’.The definition and significance of this concept were discussed in details.
