The thymus selects the useful, neglects the useless and destroys the harmful

Boehmer, Harald von; Teh, Hung Sia; Kisielow, Paweł

doi:10.1016/0167-5699(89)90307-1

Cited by 346 publications

(133 citation statements)

References 25 publications

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“…The immediate set of reactions following a trauma such as acute inflammation is referred to as the acute phase response, where IL-1, IL-6 and TNF-a are the most prominent cytokines produced. These cytokines stimulate the hypothalamicpituitary-adrenal (HPA) axis and induce the release of glucocorticoids (GC) both in vivo [24] and in vitro [25]. GC have been shown to be one of the main mediators of DP thymocyte-induced apoptosis, and thymic involution does not occur in adrenalectomized animals [26,27].…”

Section: Discussionmentioning

confidence: 99%

Dextran Sulfate Sodium‐induced Colitis Generates a Transient Thymic Involution – Impact on Thymocyte Subsets

et al. 2007

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One of the most widely used animal models for inflammatory bowel disease (IBD) is the dextran sulfate sodium (DSS)‐induced colitis. We have previously reported that 5 days administration of DSS in C57Bl/6J mice induces a colonic inflammation that progresses into chronicity after DSS removal, whereas in BALB/cJ mice the inflammation resolves within 4 weeks post‐DSS. Here we show that both thymic size and thymocyte numbers dramatically decreased in the acute phase of inflammation in C57Bl/6 mice, 7 days after DSS withdrawal. Mature, CD4+ and CD8+ single positive (SP) CD69lo CD62Lhi thymocytes were enriched in these mice, accompanied by a major decrease in the number of immature double positive (DP) thymocytes. However, the different maturation stages within the DP thymocyte subset were unchanged between healthy and inflamed C57Bl/6J mice. Interestingly, as the inflammation progressed into the chronic phase, the thymus recovered and 2 weeks after the acute inflammatory phase all the thymic parameters investigated in this study were restored to normal. In contrast, BALB/cJ mice only develop mild thymic alterations. Nevertheless, we found that within the double negative (DN) thymocytes an increased frequency and also total numbers of CD44+ CD25− (DN1) cells correlated with the severety of colitis, and that the frequency of CD44− CD25− (DN4) thymocytes decreased proportionally in the acute phase in BALB/cJ mice. Our observations suggest that the thymic effects are intimately connected to the intestinal inflammatory response in colitis regardless of the inflammatory stimuli.

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Section: Discussionmentioning

confidence: 99%

Dextran Sulfate Sodium‐induced Colitis Generates a Transient Thymic Involution – Impact on Thymocyte Subsets

et al. 2007

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“…Because of the unpredictable diversity in their binding specificity, the differentiation and survival of precursor T cells include a test of the recognition properties of these somatically generated receptors against the internal antigenic environment (1)(2)(3)(4). A key aspect of this process involves the death of developing thymocytes with TCR whose interactions with self Ags (short peptides bound to MHC molecules) might result in full activation of the mature T cell bearing that TCR (5,6).…”

Section: Opening a Window On Thymic Positive Selection: Developmentalmentioning

confidence: 99%

Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement

Lucas

Germain

2000

The Journal of Immunology

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How TCR and non-TCR signals are integrated by thymocytes to generate a decision to undergo either positive or negative selection remains incompletely understood. Recent evidence suggests that TCR signal transduction changes its quality during thymocyte maturation, but whether the contributions of various cosignaling or costimulatory pathways to thymocyte selection also are modified during development is unclear. Questions also remain about the possible selective roles of specific costimulatory pathways in induction of differentiation vs death among thymocytes at any given stage of maturity. To address these issues, a quantitative in vitro analysis of initiation of CD4+CD8+ thymocyte differentiation as measured by CD69 up-regulation/coreceptor down-modulation was conducted in parallel with an analysis of induction of death. Using transfected cells varying in their surface display of ICAM-1 or B7.1 along with antibody blocking experiments, we demonstrate here that ICAM-1 provides a selective boost to signaling for differentiation without substantially affecting induction of death among CD4+CD8+ cells, a property that is lost as thymocytes mature further. In contrast, B7 engagement enhances both cell activation and death in parallel. Based on these data, we propose that the high level of ICAM-1 on cortical epithelial cells plays a special role in opening a window between TCR signaling for differentiation vs death, permitting efficient initiation of positive selection on epithelial ligands. In contrast, late CD28-dependent cosignaling on hemopoietic cells in the medulla would help enforce negative selection by augmenting the effects of TCR engagement by low levels of high affinity ligands.

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“…Negative selection induces the death of thymocytes with TCRs whose interactions with self peptide/MHC molecule ligands might result in full activation of mature T cells and autoimmune responses (2,31). Thymocytes also require TCR-mediated signals for survival, maturation, and the choice between the CD4 ϩ and CD8 ϩ lineages (32), all these processes being part of positive selection.…”

Section: Discussionmentioning

confidence: 99%

“…Thymocytes with TCRs unable to perceive self peptide/MHC complexes die by neglect. Thus, postrearrangement-selective mechanisms allow death by neglect of the useless, active elimination of the dangerous, and survival of the useful (2). Self peptide/MHC molecules are crucial in the generation of a T cell repertoire with a wide spectrum of specificities.…”

Section: Quantitative and Qualitative Adjustment Of Thymic T Cell Promentioning

confidence: 99%

Quantitative and Qualitative Adjustment of Thymic T Cell Production by Clonal Expansion of Premigrant Thymocytes

Campion

Lucas

Dautigny

et al. 2002

The Journal of Immunology

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In normal mice, single-positive thymocytes proliferate before being exported into the peripheral T cell pool. We measured the in vivo proliferation rates of mature thymocytes in several TCR transgenic mice. Different monoclonal TCR transgenic single-positive thymocytes proliferated at different rates in a given MHC context. Conversely, mature thymocytes expressing a given TCR, generated in mice of different MHC haplotypes, also showed different rates of proliferation. In p59fyn-deficient mice, the proliferation rate of mature thymocytes was diminished. Thus, premigrant thymocyte expansion is TCR mediated and depends on TCR affinity for self peptide/MHC ligands. In addition, we show that mature thymocyte expansion is clonotypic, increases the daily thymic T cell output, and modifies the TCR repertoire of newly produced T cells.

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The thymus selects the useful, neglects the useless and destroys the harmful

Cited by 346 publications

References 25 publications

Dextran Sulfate Sodium‐induced Colitis Generates a Transient Thymic Involution – Impact on Thymocyte Subsets

Dextran Sulfate Sodium‐induced Colitis Generates a Transient Thymic Involution – Impact on Thymocyte Subsets

Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement

Quantitative and Qualitative Adjustment of Thymic T Cell Production by Clonal Expansion of Premigrant Thymocytes

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