BACKGROUND: Little is known about the CD98 heavy chain (CD98hc) in the T lymphocyte-mediated immune response to alloantigen. METHODS: We used an in vitro mixed leukocyte reaction assay and a cardiac transplantation model to evaluate the mechanisms of CD98hc in regulating alloimmune responses. RESULTS: A T cell-specific deficiency of CD98hc resulted in lower responses to alloantigen stimulation in a mixed leukocyte reaction assay, and CD98hc-deficient mice accepted full major histocompatibility complex-mismatched cardiac allografts. Consistent with graft survival, the infiltration of the graft by immune cells in CD98hc-deficient mice was significantly lower than that in wild-type mice. A chemotaxis assay revealed the migration of CD98hc-deficient lymphocytes to decrease in the presence of CCL5 compared with wild-type cells. Moreover, the proportion of CD4/Foxp3-positive cells and Foxp3 messenger RNA increased significantly in CD98hc-deficient recipients, consistent with the down-regulation of mammalian target of rapamycin and PS6 kinase; and allograft permanent acceptance was shortened by the depletion of antibody-induced regulatory T cells. Finally, neutralizing antibody against CD98hc prolonged the cardiac allograft survival. CONCLUSIONS: Taken together, our data indicate that T cell-specific deficiency in CD98hc can contribute to cardiac allograft permanent acceptance correlating with the attenuation of lymphocyte migration and by increasing the generation of regulatory T cells. These findings are expected to make it possible to develop novel approaches for treating allograft rejection and promoting transplantation tolerance.
BACKGROUND: Little is known about the CD98 heavy chain (CD98hc) in the T lymphocyte-mediated immune response to alloantigen. METHODS: We used an in vitro mixed leukocyte reaction assay and a cardiac transplantation model to evaluate the mechanisms of CD98hc in regulating alloimmune responses. RESULTS: A T cell-specific deficiency of CD98hc resulted in lower responses to alloantigen stimulation in a mixed leukocyte reaction assay, and CD98hc-deficient mice accepted full major histocompatibility complex-mismatched cardiac allografts. Consistent with graft survival, the infiltration of the graft by immune cells in CD98hc-deficient mice was significantly lower than that in wild-type mice. A chemotaxis assay revealed the migration of CD98hc-deficient lymphocytes to decrease in the presence of CCL5 compared with wild-type cells. Moreover, the proportion of CD4/Foxp3-positive cells and Foxp3 messenger RNA increased significantly in CD98hc-deficient recipients, consistent with the down-regulation of mammalian target of rapamycin and PS6 kinase; and allograft permanent acceptance was shortened by the depletion of antibody-induced regulatory T cells. Finally, neutralizing antibody against CD98hc prolonged the cardiac allograft survival. CONCLUSIONS: Taken together, our data indicate that T cell-specific deficiency in CD98hc can contribute to cardiac allograft permanent acceptance correlating with the attenuation of lymphocyte migration and by increasing the generation of regulatory T cells. These findings are expected to make it possible to develop novel approaches for treating allograft rejection and promoting transplantation tolerance.
Authors: Q Zhang; N Ichimaru; S Higuchi; S Cai; J Hou; M Fujino; N Nonomura; M Kobayashi; H Ando; A Uno; K Sakurai; S Mochizuki; Y Adachi; N Ohno; H Zou; J Xu; X-K Li; S Takahara Journal: Gene Ther Date: 2015-01-08 Impact factor: 5.250
Authors: Linda V Sinclair; Julia Rolf; Elizabeth Emslie; Yun-Bo Shi; Peter M Taylor; Doreen A Cantrell Journal: Nat Immunol Date: 2013-03-24 Impact factor: 25.606