SunlmaryT cell activation requires two distinct signals. The first is delivered through the antigen-specific T cell receptor (TCR), and the second is provided by costimulatory molecule(s) present on the surface of the antigen-presenting cell (APC). Stimulation of T helper type 1 T cell clones through the TCR in the absence of the costimulatory activity results in a lack of interleukin 2 (IL-2) secretion and proliferation, and the induction of a long-lived state of nonresponsiveness, termed anergy. In this study, we have examined the transcription factors involved in IL-2 gene expression that are expressed after stimulation of normal T cell clones through the TCR with and without engagement of the necessary costimulatory molecule(s). Antigen-specific activation of the clones results in the induction of a similar pattern of transcription factors that have been previously shown to regulate IL-2 expression. In contrast, antigen presentation by chemically fixed APC, a condition that results in T cell anergy, induces neither NF-AT nor one of the two NF-IcB binding factors. Thus, the failure to express IL-2 during the induction of T cell anergy may be attributed to the absence of these two transcription factors. When anergized T cells are restimulated with antigen and conventional APC, they induce the transcription factors associated with IL-2 expression, but they fail to synthesize measurable IL-2. Taken together, these data indicate that the control of IL2 gene expression during anergy induction and during normal stimulation of anergized cells are distinct, and suggest the presence of additional regulatory elements in the IL-2 gene.
Mutations in the transforming growth factor b type II receptor (TGFbRII) have been found in various malignant tumors, suggesting that loss of TGFb signaling plays a causal role in late-stage cancer development. To test whether loss of TGFbRII is involved in early-stage carcinogenesis, we have generated transgenic mice expressing a dominant negative TGFbRII (DbRII) in the epidermis. These mice exhibited an increased susceptibility to chemical carcinogenesis protocols at both early and late stages. In the current study, parameters for cell cycle progression and chromosome instability were analysed in DbRII tumors. DbRII papillomas showed an increased S phase in¯ow cytometry. Bromodeoxyuridine (BrdU) labeling and mitotic indices in DbRII papillomas also showed a threefold increase compared to papillomas developing in non-transgenic mice. When papillomas further progressed to squamous cell carcinomas (SCC), both control and DbRII SCC showed similar BrdU labeling indices and percentages of S phase cells. However, DbRII SCC cells showed a sixfold increase in the G2/M population. Mitotic indices in DbRII SCC also showed a threefold increase compared to non-transgenic SCC. Consistent with a perturbed cell cycle, DbRII papillomas and SCC showed reduced expression of the TGFb target genes p15 (INK4b), p21 (WAF-1) and p27 (Kip1), inhibitors of cyclin-dependent kinases (cdks). However, most DbRII papilloma cells exhibited normal centrosome numbers, and DbRII SCC exhibited a similar extent of centrosome abnormalities compared to control SCC (35 ± 40% cells). Most of DbRII SCC exhibited diploid chromosome pro®les. These data indicate that inactivation of TGFbRII accelerates skin tumorigenesis at early stages by the acceleration of loss of cell cycle control, but not by increased chromosome instability. Oncogene (2000) 19, 3623 ± 3631.
CD4+ T cells have been described to have both helper and lytic function. The helper function of Th1 cells in particular can be inactivated by inducing the T cell into a state of nonresponsiveness in which the T cell is no longer capable of producing IL-2 or proliferating in an autocrine way to a conventional antigenic stimulus. To determine whether the lytic ability of Th1 cells can also be rendered nonfunctional upon anergy induction, we induced Th1 clones into a nonresponsive state and tested their ability to lyse target cells in an Ag-specific and MHC class II-restricted manner. We show that cells newly induced into an anergic state were able to lyse target cells nonspecifically. This effect was short-lived and after resting in culture media, the cells regained their ability to lyse target cells in an Ag/MHC-specific manner, and this ability was comparable to normal resting T cells. In contrast, the helper function of these cells remained nonresponsive, and the cells were unable to proliferate or to secrete IL-2 in response to the same antigenic stimulus used for lysis. Therefore, the lytic pathway appears to be regulated separately from the proliferative/lymphokine pathway(s) and is not affected long-term by an anergic stimulus.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.