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Persistent lymphocytosis in large granular lymphocyte leukemia (LGL) may result from defects in activation- or Fas crosslinking-induced cell death. Here we show that Fas crosslinking and CD3 activation causes apoptosis of in vitro activated CD8 T cells, but not of freshly isolated CD8 T cells. Death was partially blocked by a neutralizing antibody to FasL. Inhibition of metalloproteinase-mediated FasL solubilization significantly potentiated induction of cell death. Furthermore, CD3 plus CD28 stimulation resulted in telomeric erosion in LGL cells, and ultimately proliferation ceased. Together, these data indicate that activation- and proliferation-related cell death mechanisms are functional in LGL cells.

TGF-beta and hypothized that some tumor antigens may drive CD4+ T cells into Th3 cells. Alpha-fetoprotein (AFP) is an oncofetal antigen and we had shown that it has intrinsic immunoregulatory properties. Aims: Here, we aimed to a. Identify Th3 epitopes within AFP sequence and study phenotypic and functional properties of AFP-specific Th3 cells in HCC patients and healthy donors. b. Study The effects of chem./embolisation on AFP-Th3 and Th1 responses. Methods: Short term T cell lines and T cell clones were generated in vitro. Peptide recognition was analyzed using ELISA, ELISPOT and intracellular cytokine assays. Phenotypic characterization of cytokine producing AFPspecific Th3 lines and clones were analyzed using six color flow cytometry. Standard T cell inhibition and transwell experiments were performed with or without blocking antibodies. Results: we report the identification and characterization of subsets of CD4+ T cells that recognize an epitope within AFP sequence and develop into TGF-beta producing CD4+ T cells. In a peptide specific and dose dependent manner, AFP CD4+ T cells produce TGF-beta, but not Th1, Th2, Th17 or Tr1 type cytokines. These cells express CD3, CD4, CTLA-4 and GITR but did not express Foxp3. Several AFP-Th3 cell clones from HCC patients and healthy donors were generated and characterized. Some AFP-Th3 clones inhibited T cell proliferation in vitro in a contact dependent manner. The frequency of AFP Th3 cells is significantly higher (p = 001) in patients with HCC than in healthy donors, suggesting that these cells are expanded in response to tumor antigen. In contrast, tumor necrosisinducing treatment (embolisation) that is shown to improve survival rate, can shift Th1/Th3 cells balance in favor of AFP-Th1 responses. Conclusion: Our data demonstrate that tumor antigens may contain epitopes which activate the expansion of inducible Treg cells, leading to evasion of tumor control.