Small cortical thymocytes are subject to positive selection.

Lundberg, Katarina; Shortman, Ken

doi:10.1084/jem.179.5.1475

Cited by 33 publications

(22 citation statements)

References 45 publications

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“…To test if Dlg1 loss may exert quantitative, or perhaps more subtle, effects during selection of immature thymocytes we used a competitive intrathymic transfer approach similar to that previously published [26,27]. In these experiments we used CFSElabeled double-positive (DP) thymocytes isolated from OT2transgenic Dlg1-deficient (KO) or -sufficient (WT) mice, which were mixed at a 1:1 ratio and subsequently injected directly into the thymus of unmanipulated C57BL/6 recipients at a dose of 4 × 10 6 cells/mouse and analyzed 3 days later for developmental progression.…”

Section: Dlg1 Is Dispensable For the Differentiation Of αβ-Lineage Thmentioning

confidence: 99%

Polarity gene discs large homolog 1 regulates the generation of memory T cells

et al. 2013

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SUMMARY Mammalian ortholog of Drosophila cell polarity protein, Dlg1, plays a critical role in neural synapse formation, epithelial cell homeostasis, and urogenital development. More recently, it has been proposed that Dlg1 may also be involved in the regulation of T-cell proliferation, migration, and antigen receptor signaling. However, a requirement for Dlg1 in development and function of T lineage cells remains to be established. In this study, we investigated a role for Dlg1 during T-cell development and function using a combination of conditional Dlg1 knockout and two different Cre expression systems where Dlg1 deficiency is restricted to the T-cell lineage only, or all hematopoietic cells. Here, using three different TCR models, we show that Dlg1 is not required during development and selection of thymocytes bearing functionally rearranged TCR transgenes. Moreover, Dlg1 is dispensable in the activation and proliferative expansion of antigen specific TCR transgenic CD4+ and CD8+ T cells in vitro and in vivo. Surprisingly, however, we show that Dlg1 is required for normal generation of memory T cells during endogenous response to cognate antigen. Thus, Dlg1 is not required for the thymocyte selection or the activation of primary T cells, however it is involved in the generation of memory T cells.

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Section: Dlg1 Is Dispensable For the Differentiation Of αβ-Lineage Thmentioning

confidence: 99%

Polarity gene discs large homolog 1 regulates the generation of memory T cells

et al. 2013

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“…Double Tg bcl-2+Db/HY TCR mice show that constitutive expression of bcl-2 increases the survival of thymocytes in the absence of positive selection (34)(35)(36). The bcl-2 transgene also reduces the efficiency of negative selection, but the mature peripheral T cells that appear in increased numbers are not autoreactive.…”

mentioning

confidence: 99%

“…Other apoptosis pathways exist in the thymus in vivo and these pathways may operate at different developmental stages of thymocytes or in association with different signaling events in addition to anti-CD3. Increased T cell survival during negative selection has been observed in bcl-2/Db/Hy TCP,.-a//3 double Tg mice (34)(35)(36). Increased survival of Single ceil suspensiom were prepared from LN of IY~ TCK Tg male and ANur77-Db/Hy TCK double Tg male mice.…”

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confidence: 99%

Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.

Zhou

Cheng

Yang

et al. 1996

The Journal of Experimental Medicine

149

114

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SummaryThe Nur77/Nurrl family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)-mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (ANur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-[3 enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8 + thymocytes mediated by CD3/TCR signaling was greatly inhibited in the ANur77 Tg mice, compared with non-Tg littermates, after treatment with anti-CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self-reactive T cells was investigated in ANur77-Db/HY TCR-ot/~3 double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-et/~3 in the ANur77-TCR-ot/[3 double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8 + thymocytes that expressed Tg TCR-a/[~. There was an eight-fold increase in CD8 +, DB/Hy TCR-ot/[3 T cells in the lymph nodes (LN) of ANur77-Db/Hy TCR-o_/[3 double Tg compared with Db/Hy TCR-0~/I3 Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of ANur77-Db/Hy TCR-oJI3 double Tg male mice. These results indicate that inhibition of Nur77/Nurrl DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen.

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“…In reaggregate thymic organ cultures (RTOC), DP TCR-negative cells generate CD4 SP cells before CD8 SP cells (9). Adoptive transfer experiments using purified adult DP subsets also demonstrated that differentiation into CD8 SP thymocytes needs longer than differentiation into CD4 SP cells (10). Utilizing a marker (F3) differentially expressed on pre-selection and post-selection DP thymocytes, we have previously ob-served that post-selection DP cells generate both CD8 and CD4 SP cells within 48 h of RTOC, whereas pre-selection DP cells generate only CD4 SP cells under these conditions (11).…”

Section: Discussionmentioning

confidence: 99%

Asynchronous Coreceptor Downregulation after Positive Thymic Selection: Prolonged Maintenance of the Double Positive State in CD8 Lineage Differentiation Due to Sustained Biosynthesis of the CD4 Coreceptor

Barthlott

Kohler

Eichmann

1997

The Journal of Experimental Medicine

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In several experimental systems analyzing the generation of single positive (SP) thymocytes from double positive (DP) thymocytes, CD4 SP cells have been shown to appear before CD8 SP cells. This apparent temporal asymmetry in the maturation of CD4 SP and CD8 SP thymocytes could either be due to divergent molecular differentiation programs of the two T cell lineages, or merely to slower degradation kinetics of the CD4 protein. To study this question in unmanipulated in vivo differentiation, we developed a four-color flow cytometry protocol which identifies a recently activated TCRintCD69pos thymocyte population containing DP cells and early CD4 SP cells but no CD8 SP cells. We show that these TCRintCD69pos thymocytes represent a transitory stage in the mainstream αβ T cell lineage. The precursors of the CD8 SP cells are contained in this population as incompletely selected DP cells. Moreover, we show that expression of both coreceptors in the TCRintCD69pos population depends on transcriptional and translational activity, thus excluding differences in turnover rates of the CD4 and CD8 proteins as the cause of the asynchrony in differentiation of the CD4 and CD8 lineages.

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Small cortical thymocytes are subject to positive selection.

Cited by 33 publications

References 45 publications

Polarity gene discs large homolog 1 regulates the generation of memory T cells

Polarity gene discs large homolog 1 regulates the generation of memory T cells

Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.

Asynchronous Coreceptor Downregulation after Positive Thymic Selection: Prolonged Maintenance of the Double Positive State in CD8 Lineage Differentiation Due to Sustained Biosynthesis of the CD4 Coreceptor

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