T cell development and function in complex ganglioside-lacking (GM2/GD2 synthase gene-disrupted) mice were analyzed. GM1, asialo-GM1, and GD1b were representative gangliosides expressed on T cells of the wild type mice and completely deleted on those of the mutant mice. The sizes and cell numbers of the mutant mice spleen and thymus were significantly reduced. Spleen cells from the mutant mice showed clearly reduced proliferation compared with the wild type when stimulated by interleukin 2 (IL-2) but not when treated with concanavalin A or anti-CD3 cross-linking. Expression levels of IL-2 receptor alpha, beta, and gamma were almost equivalent, and up-regulation of alpha chain after T cell activation was also similar between the mutant and wild type mice. Activation of JAK1, JAK3, and SAT5 after IL-2 treatment was reduced, and c-fos expression was delayed and reduced in the mutant spleen cells, suggesting that the IL-2 signal was attenuated in the mutant mice probably due to the modulation of IL-2 receptors by the lack of complex gangliosides.
A mouse HER2‐derived peptide, HER2p63 (A) (TYLPANASL), can induce Kd‐restricted mouse cytotoxic T lymphocytes (CTL) and also function as a tumor rejection antigen in an in vivo assay. Since the anchor motif of mouse Kd for peptide binding has much similarity to that of human HLA‐A2402, we asked if human HER2p63 (T) (TYLPTNASL) could induce HER2‐specific CTL in HLA‐A2402‐positive individuals. Peripheral blood mononuclear cells (PBMC) of HLA‐A2402‐positive individuals were sensitized in vitro with HER2p63‐pulsed autologous dendritic cells prepared from PBMC. CTL clone derived from these specifically lysed HER2‐expressing cell lines bearing HLA‐A2402. Cytotoxic activity of the CTL clone against the HER2‐expressing cell line bearing HLA‐A2402 was blocked by antibodies against CD3, CD8, HLA‐A24 or MHC class I, and was also inhibited by the addition of excess HER2p63‐pulsed C1R bearing HLA‐A2402. Killer cells were generated from PBMC of seven healthy individuals and five ovarian cancer patients, all of HLA‐A2402 type, by in vitro sensitization with HER2p63‐pulsed autologous antigen presenting cells. These killer cells selectively lysed HER2‐expressing SKOV3 transfected with HLA‐A2402 cDNA, indicating high immunogenicity of HER2p63 in all 12 individuals examined.
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