ABSTRACT
Activation-induced cell death (AICD) plays a critical role in immune homeostasis and tolerance. In T-cell-dependent humoral responses, AICD of B cells is initiated by Fas ligand (FasL) on T cells, stimulating the Fas receptor on B cells. In contrast, T-cell-independent B cell responses involve innate-type B lymphocytes, such as marginal zone (MZ) B cells, and little is known about the mechanisms that control AICD during innate B cell responses to Toll-like receptor (TLR) activation. Here, we show that MZ B cells undergo AICD in response to TLR4 activation in vivo. The transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor and TLR4 cooperate to upregulate expression of both FasL and Fas on MZ B cells and also to repress inhibitors of Fas-induced apoptosis signaling. These findings demonstrate an unappreciated role for TACI and its ligands in the regulation of AICD during T-cell-independent B cell responses.
Subject(s)
Apoptosis , Fas Ligand Protein/metabolism , Toll-Like Receptor 4/metabolism , Transmembrane Activator and CAML Interactor Protein/metabolism , fas Receptor/metabolism , Animals , B-Cell Activation Factor Receptor/biosynthesis , B-Lymphocytes/immunology , Enzyme Activation , Fas Ligand Protein/biosynthesis , Lipopolysaccharides , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Transmembrane Activator and CAML Interactor Protein/geneticsABSTRACT
Activin is a pleiotropic cytokine with broad tissue distributions. Recent studies demonstrate that activin-A inhibits cancer cell proliferation with unknown mechanisms. In this report, we demonstrate that recombinant activin-A induces telomerase inhibition in cancer cells. In breast and cervical cancer cells, activin-A resulted in telomerase activity in a concentration-dependent manner. Significant inhibition was observed at 10 ng/ml of activin-A, with a near complete inhibition at 80 ng/ml. Consistently, activin-A induced repression of the telomerase reverse transcriptase (hTERT) gene, with the hTERT gene to be suppressed by 60-80% within 24h. In addition, activin-A induced a concomitant increase in Smad3 signaling and decrease of the hTERT gene promoter activity in a concentration-dependent fashion. These data suggest that activin-A triggered telomerase inhibition by down-regulating hTERT gene expression is involved in activin-A-induced inhibition of cancer cell proliferation.
Subject(s)
Activins/pharmacology , Neoplasms/enzymology , Telomerase/antagonists & inhibitors , Tumor Suppressor Proteins/pharmacology , Down-Regulation , HeLa Cells , Humans , Recombinant Proteins/pharmacology , Telomerase/genetics , Telomerase/metabolismABSTRACT
Human telomerase reverse transcriptase (hTERT) represents a universal tumor-associated antigen to activate specific immune response in cancer immune therapy. Peptides derived from hTERT are presented by major histocompatibility complex (MHC) class I alleles to T lymphocytes, and CD8+ cytotoxic T lymphocytes (CTLs) specific for the hTERT-derived antigenic epitopes lyse hTERT-positive tumors from multiple histologies. These findings identify hTERT as an important tumor antigen widely applicable for anti-cancer immunotherapeutic strategies. The hTERT antigen-specific immunotherapy involves both active vaccination and adoptive immunotherapy approaches. Most importantly, the anti-tumor immune responses have been observed in the absence of toxicity, underlying the ongoing endeavors to develop immunotherapy directed against hTERT antigen. This chapter discusses most promising results and the approaches for investigation to target hTERT peptides as tumor antigens.
