The dose-dependent α-fetoprotein (AFP) reactivity of different types of tumor cells and normal embryonal fibroblasts, which are capable of taking up AFP, was investigated. High doses (more than 100 µg/ml) of purified human AFP were shown to induce strongly dose-dependent growth inhibition of human hepatoma HepG2 cells, human lymphoblastoma MT4 cells, lymphoma Jurkat cells and murine fibroblastoma L929 cells. Human mammary carcinoma MCF-7 cells also revealed a growth inhibitory response to AFP, although to a lesser extent. Equivalent doses of human serum albumin (HSA) demonstrated no effect on these cells. On the contrary, normal embryonal fibroblasts of different organ origin showed dose-dependent stimulation (50–90%) of proliferation in response to AFP. A similar stimulative effect was obtained when embryonal fibroblasts were treated with the same doses of HSA. The myeloblastoma cell line U-937 and the normal epidermal fibroblast cell line M19 were shown to be resistant to the AFP action over a wide range of protein concentrations. It was demonstrated that growth factor deprivation (i.e. low serum concentration) could stimulate U-937 cell proliferation in response to high doses of AFP. It was also shown that intensive washing of U-937 and MCF-7 cells with fresh medium to remove secreted cytokines and growth factors distinctly increased cell sensitivity to high-dose-AFP-induced growth-inhibitory activity. Low AFP concentrations (less than 100 µg/ml) failed to induce growth inhibition in all studied cells and rather showed a slight stimulative effect. These findings demonstrate that physiological levels of AFP can exhibit a dose-dependent growth-regulatory activity toward sensitive tumor or developing cells. Our data demonstrated that AFP could reveal either stimulative or inhibitory growth activity, depending on the relative concentration of AFP and on exogenous or endogenous cytokines and growth factors in the cell culture medium. A growth-stimulative activity in normal embryonal fibroblasts and certain tumor cell lines exhibited by low AFP concentrations is supposed to result from the synergistic effects of AFP and various other secreted growth factors.

No abstract

Both TCRα and TCRβ types of T-cell receptors contribute to antigen recognition. However, some TCRs have chain centricity, which means that either the α-chain or the β-chain dictates the peptide-MHC complex specificity. Most earlier reports investigated the role of well-studied β-chains in antigen recognition by TCRαβ. In a previous study, we identified TCRs specific to the H-2K b molecule. In the present work, we generated transgenic mice carrying the α-chain of this TCR. We found that these transgenic mice rejected EL-4 tumor cells bearing alloantigen H-2K b more effectively than wild-type mice and similarly to mice with established specific memory T cells. Moreover, we found that T cells transduced with this TCRα can inhibit EL-4 cell growth in vitro and in vivo. We also found that transgenic mice recruit fewer CD8 T cells into the peritoneal cavity at the peak of the immune response and had a significantly higher number of central memory CD8 T cells in the spleen of intact transgenic mice compared to intact wild-type control. These results indicate the ability of a single transgenic α-chain of the H-2K b-specific TCR to determine specific recognition of the H-2K b molecule by a repertoire of T lymphocytes and to rapidly reject H-2K b-bearing lymphoma cells.

No abstract

Peripheral T lymphocytes can be subdivided into naïve and antigen-experienced T cells. The latter, in turn, are represented by effector and central memory cells that are identified by different profiles of activation markers expression, such as CD44 and CD62L in mice. These markers determine different traffic of T lymphocytes in the organism, but hardly reproduce real antigenic experience of a T lymphocyte. Mechanisms of homeostasis maintenance of T lymphocytes with different activation phenotypes remain largely unknown. To investigate impact of T cell receptor (TCR) transgenic chains on formation of T lymphocytes, their peripheral survival and activation surface phenotypes, we have generated the transgenic mouse strain expressing transgenic β-chain of TCR 1D1 (belonging to the Vβ6 family) on the genetic background B10.D2(R101). Intrathymic development of T cells in these transgenic mice is not impaired. The repertoire of peripheral T lymphocytes in these mice contains 70-80% of T cells expressing transgenic β-chain and 20-30% of T cells expressing endogenous β-chains. The ratio of peripheral CD4⁺CD8⁻ and CD4⁻CD8⁺ T lymphocytes remained unchanged in the transgenic animals, but the percent of T lymphocytes with the "naïve" phenotype CD44⁻CD62L⁺ was significantly increased, whereas the levels of effector memory CD44⁺CD62L⁻ and central memory CD44⁺CD62L⁺ T lymphocytes were markedly decreased in both subpopulations. On the contrary, T lymphocytes expressing endogenous β-chains had surface phenotype of activated T cells CD44⁺. Thus, for the first time we have shown that the pool of T lymphocytes with different activation phenotypes depends on the structure of T cell receptors.