Increased p300 Expression Inhibits Glucocorticoid Receptor-T-Cell Receptor Antagonism but Does Not Affect Thymocyte Positive Selection

ABSTRACT Positive selection of T cells is postulated to be dependent on the counterinteraction between glucocorticoid receptor (GR)- and T-cell-receptor (TCR)-induced death signals. In this study we used T-cell-specific expression of p300 to investigate whether GR-TCR cross talk between thymocytes was affected. Activation of the p300-transgenic T cells led to enhanced thymocyte proliferation and increased interleukin 2 production. Thymocyte death, induced by TCR engagement, was no longer prevented by dexamethasone in p300-transgenic mice, indicating an absence of GR-TCR cross-inhibition. This was accompanied by a 50% reduction in the number of thymocytes in p300-transgenic mice. However, the CD4/CD8 profile of thymocytes remained unchanged in p300-transgenic mice. There was no effect on positive selection of the bulk thymocytes or thymocytes with transgenic TCR in p300-transgenic mice. In addition, there was no apparent TCR repertoire “hole” in the selected antigens examined. Our results illustrate a critical role of CBP/p300 in thymic GR-TCR counterinteraction yet do not support the involvement of GR-TCR antagonism in thymocyte positive selection.

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Early Deletion and Late Positive Selection of T-Cells Expressing a Male-Specific Receptor in T-Cell Receptor Transgenic Mice

Developmental Immunology ◽

10.1155/1990/18208 ◽

1990 ◽

Vol 1 (1) ◽

pp. 1-10 ◽

Cited By ~ 52

Author(s):

Hung Sia Teh ◽

Hiroyuki Kishi ◽

Bernadette Scott ◽

Peter Borgulya ◽

Harald Von Boehmer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Positive Selection ◽

T Cell Receptor ◽

Interleukin 2 ◽

Cell Receptor ◽

Early Expression ◽

Single Positive ◽

Selection Of

The ontogeny of T cells in T-cell receptor (TCR) transgenic mice, which express a transgenicαβheterodimer, specific for the male (H-Y) antigen in association with H-2Db, was determined. The transgenicαchain was expressed on about 10% of the fetal thymocytes on day 14 of gestation. About 50% of day-15 fetal thymocytes expressed bothαandβtranschains and virtually all fetal thymocytes expressed the transgenicαβheterodimer by day 17. The early expression of the transgenic TCR on CD4-8-thymocytes prevented the development ofγδcells, and led to accelerated growth of thymocytes and an earlier expression of CD4 and CD8 molecules. Up to day 17, no significant differences in T-cell development could be detected between female and male thymuses. By day 18 of gestation, the male transgenic thymus contained more CD4-8-thymocytes than the female transgenic thymus. The preponderance of CD4-8-thymocytes in the male transgenic thymus increased until birth and was a consequence of the deletion of the CD4+8+thymocytes and their CD4-8+precursors. By the time of birth, the male transgenic thymus contained half the number of cells as the female transgenic thymus. The deletion of autospecific precursor cells in the male transgenic mouse began only at day 18 of gestation, despite the fact that the ligand could already be detected by day 16.The preferential accumulation of CD4-8+T cells, which expressed a high density of the transgenic TCR, occurred only after birth and was .obvious in 6-week-old female thymus. These data support the hypothesis that the positive selection of T cells expressing this transgenic heterodimer may involve two steps, i.e., the commitment of CD4+8+thymocytes to the CD4-8+lineage following the interaction of the transgenic TCR with restricting major histocompatibility molecules, followed by a slow conversion of CD4+8+thymocytes into CD4-8+T cells.In normal mice, the precursors of CD+4+8 and single positive thymocytes have the CD4-8-CD3-J11d+(or M1/69+) phenotype. Because of the early expression of the transgenicαβheterodimer, this population was not detected in adult transgenic mice. All CD4-8-M1/ 69+cells expressed the transgenic receptor associated with CD3 and could be readily grown in media containing T-cell lectins and interleukin 2.

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A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor–Ligand Complex

Journal of Experimental Medicine ◽

10.1084/jem.189.10.1531 ◽

1999 ◽

Vol 189 (10) ◽

pp. 1531-1544 ◽

Cited By ~ 92

Author(s):

Calvin B. Williams ◽

Deborah L. Engle ◽

Gilbert J. Kersh ◽

J. Michael White ◽

Paul M. Allen

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Receptor ◽

Cell Receptor ◽

Ligand Complex ◽

Altered Peptide Ligands ◽

Self Peptides ◽

Selection Of

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II– restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64–76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR–ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR–ligand complexes.

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Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a bcl-2 transgene.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.91.4.1376 ◽

1994 ◽

Vol 91 (4) ◽

pp. 1376-1380 ◽

Cited By ~ 99

Author(s):

A. Strasser ◽

A. W. Harris ◽

H. von Boehmer ◽

S. Cory

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

T Cell Receptor ◽

Negative Selection ◽

Cell Receptor ◽

Selection Of

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Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1408482111 ◽

2014 ◽

Vol 111 (25) ◽

pp. E2550-E2558 ◽

Cited By ~ 30

Author(s):

J. O. Ross ◽

H. J. Melichar ◽

B. B. Au-Yeung ◽

P. Herzmark ◽

A. Weiss ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Receptor Signaling ◽

T Cell Receptor Signaling ◽

Cell Receptor Signaling ◽

Selection Of

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Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.170.1.135 ◽

1989 ◽

Vol 170 (1) ◽

pp. 135-143 ◽

Cited By ~ 80

Author(s):

N S Liao ◽

J Maltzman ◽

D H Raulet

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Receptor ◽

Radiation Chimeras ◽

Gene Usage ◽

Selection Of

We report here a mAb, 14-2, reactive with TCRs that include V beta 14. The frequency of V beta 14+ T cells varies with CD4 and CD8 subset and is controlled by the H-2 genes. Thus CD8+ T cells from H-2b mice include approximately 2.3% V beta 14+ T cells while CD8+ T cells from mice expressing K kappa include greater than 8% V beta 14+ T cells. In all strains examined, 7-8% of CD4+ T cells express V beta 14. The frequent usage of V beta 14 in CD8+ T cells of K kappa-expressing mice is a result of preferential positive selection of V beta 14+ CD8+ T cells as demonstrated by analysis of radiation chimeras. These studies demonstrate that H-2-dependent positive selection occurs in unmanipulated mice. Furthermore, the results imply that positive selection, and possibly H-2 restriction, can be strongly influenced by a V beta domain, with some independence from the beta-junctional sequence and alpha chain.

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Class I MHC molecules on hematopoietic cells can support intrathymic positive selection of T cell receptor transgenic T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.96.20.11470 ◽

1999 ◽

Vol 96 (20) ◽

pp. 11470-11475 ◽

Cited By ~ 31

Author(s):

J. Zerrahn ◽

A. Volkmann ◽

M. C. Coles ◽

W. Held ◽

F. A. Lemonnier ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Receptor ◽

Hematopoietic Cells ◽

Cell Receptor ◽

Class I ◽

Class I Mhc ◽

Mhc Molecules ◽

Selection Of

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Anergy in Peripheral Memory Cd4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor

Journal of Experimental Medicine ◽

10.1084/jem.194.6.719 ◽

2001 ◽

Vol 194 (6) ◽

pp. 719-732 ◽

Cited By ~ 51

Author(s):

Saied Mirshahidi ◽

Ching-Tai Huang ◽

Scheherazade Sadegh-Nasseri

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Memory T Cells ◽

Critical Role ◽

Interleukin 2 ◽

Cell Receptor ◽

Memory Cd4 T Cells

Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4+ T cells can be rendered anergic by presentation of low densities of agonist peptide–major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2–reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti–CTLA-4 blocking antibody restored anergy in vivo.

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