The T cell receptor repertoire of CD4-8+ thymocytes is altered by overexpression of the BCL-2 protooncogene in the thymus.

Mice lacking IFN-regulatory factor (IRF)-1 have reduced numbers of mature CD8+ T cells within the thymus and peripheral lymphoid organs, suggesting a critical role of IRF-1 in CD8+ T cell differentiation. Here we show that endogenous Bcl-2 expression is substantially reduced in IRF-1−/−CD8+ thymocytes and that introduction of a human Bcl-2 transgene driven by Eμ or lck promoter in IRF-1−/− mice restores the CD8+ T cell development. Restored CD8+ T cells are functionally mature in terms of allogeneic MLR and cytokine production. In contrast to thymus-derived CD8+ T cells, other lymphocyte subsets including NK, NK T, and TCR-γδ+ intestinal intraepithelial lymphocytes, which are also impaired in IRF-1−/− mice, are not rescued by expressing human Bcl-2. Our results indicate that IRF-1 differentially regulates the development of these lymphocyte subsets and that survival signals involving Bcl-2 are critical for the development of thymus-dependent CD8+ T cells.

Section: Overexpression Of Bcl-2 Differentially Restores Development Ofmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Overexpression of Bcl-2 Differentially Restores Development of Thymus-Derived CD4−8+ T Cells and Intestinal Intraepithelial T Cells in IFN-Regulatory Factor-1-Deficient Mice

Ohteki

Maki

Koyasu

2001

“…Actually, thymocytes of Bcl-2 or Bcl-x L Tg mice show resistance to deletion induced in vivo by anti-CD3 Ab (33,34). Nevertheless, it has been reported that the negative selection of thymocytes, induced by endogenous superantigen or by H-Y Ag in H-Y Tg model, is normal in these mice (33)(34)(35). However, in contrast to these reports, Strasser (36) also reported that Tg expression of bcl-2 Tg mice diminished self Ag-reactive H-Y Tg T cells.…”

Section: Discussionmentioning

confidence: 98%

The Apoptotic Protease-Activating Factor 1-Mediated Pathway of Apoptosis Is Dispensable for Negative Selection of Thymocytes

Hara¹,

Takeda

Takeuchi³

et al. 2002

Negative selection is a process to delete potentially autoreactive clones in developing thymocytes. Programmed cell death or apoptosis is thought to play an important role in this selection process. In this study, we investigated the role of apoptotic protease-activating factor 1 (Apaf1), a mammalian homologue of CED-4, in programmed cell death during the negative selection in thymus. There was no developmental abnormality in thymocytes from newborn Apaf1−/− mice in terms of CD4 and CD8 expression pattern and thymocyte number. Clonal deletion by endogenous male H-Y Ag of Apaf1-deficient thymocytes with transgenic expression of H-Y Ag-specific TCRs (H-Y Tg/Apaf1−/− thymocytes) was normally observed in lethally irradiated wild-type mice reconstituted with fetal liver-derived hemopoietic stem cells. Clonal deletion induced in vitro by a bacterial superantigen was also normal in fetal thymic organ culture. Thus, Apaf1-mediated pathway of apoptosis is dispensable for the negative selection of thymocytes. However, H-Y Tg/Apaf1−/− thymocytes showed partial resistance to H-Y peptide-induced deletion in vitro as compared with H-Y Tg/Apaf1+/− thymocytes, implicating the Apaf1-mediated apoptotic pathway in the negative selection in a certain situation. In addition, the peptide-induced deletion was still observed in H-Y Tg/Apaf1−/− thymocytes in the presence of a broad spectrum caspase inhibitor, z-VAD-fmk, suggesting the presence of caspase-independent cell death pathway playing roles during the negative selection. We assume that mechanisms for the negative selection are composed of several cell death pathways to avoid failure of elimination of autoreactive clones.

“…Increased numbers of CD8 cells have been observed in several other transgenic mice. For example, Bcl2-or TOX-overexpressing transgenic mice show an accumulation of mature CD8 thymocytes for different reasons (36,37). It is possible that extra HBP1 molecules accelerate the rate of commitment toward the CD8 lineage at the expense of CD4 SP cell production.…”

Section: Discussionmentioning

confidence: 99%

Human High Mobility Group Box Transcription Factor 1 Affects Thymocyte Development and Transgene Variegation

Sekkali¹,

Szabat²,

Ktistaki³

et al. 2005

It has been shown previously that a human CD2 (hCD2) disabled locus control region (LCR) transgene is unable to establish an open chromatin configuration in all the T cells, and this leads to position effect variegation of the transgene. In this study we show that thymus-specific overexpression of human high mobility group box transcription factor 1 (HBP1), a transcription factor that binds a specific sequence within the hCD2 LCR, affects thymus cellularity as well as the number of CD8+ thymocytes in two independent transgenic mouse lines and increases the proportion of T cells that fully activate the transgenic locus in hCD2 variegating mice in a sequence-specific dependent manner. This finding suggests that overexpression of HBP1 can affect lineage commitment and can relieve the suppressive influence of heterochromatin, allowing thymocytes to express the variegating target locus more efficiently. These effects could be the result of direct HBP1 action on LCR activity. Alternatively, the extra HBP1 molecules may sequester repressive elements away from the LCR, thus allowing transcription permissive states to form on the transgene locus.