scholarly journals Thymus-derived Glucocorticoids Regulate Antigen-specific Positive Selection

1997 ◽  
Vol 185 (11) ◽  
pp. 2033-2038 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Jonathan D. Ashwell
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Cross Linking ◽  
Thymocyte Development ◽  
Organ Cultures ◽  
Specific Loss ◽  
Histocompatibility Complex ◽  
Glucocorticoid Production ◽  
Self Antigen

While it is generally believed that the avidity of the T cell antigen receptor (TCR) for self antigen/major histocompatibility complex (MHC) determines a thymocyte's fate, how the cell discriminates between a stimulus that causes positive selection (survival) and one that causes negative selection (death) is unknown. We have previously demonstrated that glucocorticoids are produced in the thymus, and that they antagonize deletion caused by TCR cross-linking. To examine the role of glucocorticoids during MHC-dependent selection, we examined thymocyte development in organ cultures in which corticosteroid biosynthesis was inhibited. Inhibition of glucocorticoid production in thymi from α/β-TCR transgenic mice resulted in the antigen- and MHC-specific loss of thymocytes that normally recognize self antigen/MHC with sufficient avidity to result in positive selection. Furthermore, inhibition of glucocorticoid production caused an increase in apoptosis only in CD+CD8+ thymocytes bearing transgenic TCRs that recognized self antigen/MHC. These results indicate that the balance of TCR and glucocorticoid receptor signaling influences the antigen-specific thymocyte development by allowing cells with low-to-moderate avidity for self antigen/MHC to survive.

scholarly journals Endogenous galectin-1 enforces class I–restricted TCR functional fate decisions in thymocytes

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 120-130 ◽  
Author(s):  
Scot D. Liu ◽  
Chan C. Whiting ◽  
Tamar Tomassian ◽  
Mabel Pang ◽  
Stephanie J. Bissel ◽  
...  
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Partial Agonist ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Class I ◽  
Thymocyte Development ◽  
Erk Activation ◽  
Extracellular Signal ◽  
Erk Activity

Abstract During thymocyte development, the T-cell receptor (TCR) can discriminate major histocompatibility complex (MHC)/peptide ligands over a narrow range of affinities and translate subtle differences into functional fate decisions. How small differences in TCR input are translated into absolute differences in functional output is unclear. We examined the effects of galectin-1 ablation in the context of class-I–restricted thymocyte development. Galectin-1 expression opposed TCR partial agonist-driven positive selection, but promoted TCR agonist-driven negative selection of conventional CD8+ T cells. Galectin-1 expression also promoted TCR agonist-driven CD8αα intestinal intraepithelial lymphocytes (IEL) development. Recombinant galectin-1 enhanced TCR binding to agonist/MHC complexes and promoted a negative-selection-signaling signature, reflected in intensified rapid and transient extracellular signal-regulated kinase (ERK) activation. In contrast, galectin-1 expression antagonized ERK activity in thymocytes undergoing positive selection. We propose that galectin-1 aids in discriminating TCR-directed fate decisions by promoting TCR binding to agonist/MHC complexes and enforcing agonist-driven signals, while opposing partial-agonist signals. In this way, galectin-1 widens the distinction between TCR-directed functional fate cues.

scholarly journals Paradoxical Signaling Pathways in Developing Thymocytes

2011 ◽  
Vol 14 (3) ◽  
pp. 378 ◽  
Author(s):  
Aws Alshamsan
Keyword(s):  
Cell Death ◽  
Positive Selection ◽  
Cell Fate ◽  
Negative Selection ◽  
Mapk Pathway ◽  
Erk Activation ◽  
Selection For ◽  
Kinetics Of ◽  
Level Order

ABSTRACT- Thymocytes are subjected to processes of selection during their life in the thymus; negative selection for autoreactive thymocytes and positive selection for self-MHC restricted self-tolerant cells. Interestingly, signals for positive or negative selection originate from the same receptor. More importantly, evidence showed that both death and survival signals are mediated by the MAPK pathway. The degree and order of ERK activation, but not other MAPK proteins, has been found to be different in either cases of cell fate. Therefore, it is suspected that the kinetics of ERK after activation may dictate cell death or survival. There are two important GEF proteins that are involved in Ras/ERK activation, RasGRP and SOS. It is thought that the level, order and kinetics of ERK are influenced upstream by the type of GEF. This review discusses the role of both GEF proteins in positive and negative selection and how this reflects on ERK activation. This article is open POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Major role of positive selection in the evolution of conservative segments of Drosophila proteins

2012 ◽  
Vol 279 (1742) ◽  
pp. 3409-3417 ◽  
Author(s):  
Georgii A. Bazykin ◽  
Alexey S. Kondrashov
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Rare Allele ◽  
Minor Role ◽  
Random Drift ◽  
Protein Coding ◽  
Slow Evolution ◽  
A Minor ◽  
New Mutations

Slow evolution of conservative segments of coding and non-coding DNA is caused by the action of negative selection, which removes new mutations. However, the mode of selection that affects the few substitutions that do occur within such segments remains unclear. Here, we show that the fraction of allele replacements that were driven by positive selection, and the strength of this selection, is the highest within the conservative segments of Drosophila protein-coding genes. The McDonald–Kreitman test, applied to the data on variation in Drosophila melanogaster and in Drosophila simulans , indicates that within the most conservative protein segments, approximately 72 per cent (approx. 80%) of allele replacements were driven by positive selection, as opposed to only approximately 44 per cent (approx. 53%) at rapidly evolving segments. Data on multiple non-synonymous substitutions at a codon lead to the same conclusion and additionally indicate that positive selection driving allele replacements at conservative sites is the strongest, as it accelerates evolution by a factor of approximately 40, as opposed to a factor of approximately 5 at rapidly evolving sites. Thus, random drift plays only a minor role in the evolution of conservative DNA segments, and those relatively rare allele replacements that occur within such segments are mostly driven by substantial positive selection.

scholarly journals Developmental regulation of thymocyte susceptibility to deletion by "self"-peptide.

1992 ◽  
Vol 176 (1) ◽  
pp. 213-223 ◽  
Author(s):  
L M Spain ◽  
L J Berg
Keyword(s):  
Cytochrome C ◽  
Organ Culture ◽  
Positive Selection ◽  
Negative Selection ◽  
Developmental Timing ◽  
Organ Cultures ◽  
Peptide Antigen ◽  
C Peptide ◽  
Mhc Molecules

The specificity of the T cell receptor (TCR) repertoire for foreign peptide bound to self-major histocompatibility complex (MHC) molecules is determined in large part by positive and negative selection processes in the thymus, yet the mechanisms of these selection events remain unknown. Using in vitro organ culture of thymi isolated from mice transgenic for a TCR-alpha/beta specific for cytochrome c peptide bound to I-Ek, we analyzed the developmental timing of negative selection (deletion). On the basis of the experiments described below, we conclude that all CD4+8+ thymocytes, and only CD4+8+ thymocytes, are susceptible to negative selection mediated by the cytochrome c peptide antigen. First, we found that deletion of thymocytes resulting from addition of the cytochrome c peptide to the thymic organ cultures can occur at the earliest stage of TCR, CD4, and CD8 coexpression. Second, we found that CD4+8+ thymocytes isolated from positively selecting or nonselecting MHC haplotypes were equally efficiently deleted in vitro, suggesting that positive selection is not a prerequisite for deletion. Third, we examined the effects of TCR/ligand avidity on the developmental timing of deletion by varying the concentration of cytochrome c peptide added to the organ cultures. We detected deletion only at the CD4+8+ stage: intermediate concentrations of peptide that resulted in partial deletion of CD4+8+ cells did not eliminate the appearance of mature CD4+8- cells. Finally, we found that CD4+8- thymocytes were resistant to deletion as well as activation by peptide antigen added to the intact organ cultures. Nevertheless, the CD4+8- thymocytes isolated from the peptide-treated organ cultures responded vigorously to peptide presented by spleen cells in vitro. Thus, the T cells were tolerant of (but not anergized by) self-antigen encountered in thymic organ culture. Together, these results indicate that thymocytes susceptible to negative selection are not developmentally distinct from those susceptible to positive selection, and further, that the thymic microenvironment plays a role in regulating the outcome of TCR/ligand interactions.

scholarly journals Peptide-MHC heterodimers show that thymic positive selection requires a more restricted set of self-peptides than negative selection

2010 ◽  
Vol 207 (6) ◽  
pp. 1223-1234 ◽  
Author(s):  
Jeremy Juang ◽  
Peter J.R. Ebert ◽  
Dan Feng ◽  
K. Christopher Garcia ◽  
Michelle Krogsgaard ◽  
...  
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
T Cell Receptors ◽  
Negative Selection ◽  
Peptide Ligands ◽  
Cell Selection ◽  
Altered Peptide Ligands ◽  
Endogenous Peptides ◽  
Histocompatibility Complex ◽  
T Cell Selection

T cell selection and maturation in the thymus depends on the interactions between T cell receptors (TCRs) and different self-peptide–major histocompatibility complex (pMHC) molecules. We show that the affinity of the OT-I TCR for its endogenous positively selecting ligands, Catnb-H-2Kb and Cappa1-H-2Kb, is significantly lower than for previously reported positively selecting altered peptide ligands. To understand how these extremely weak endogenous ligands produce signals in maturing thymocytes, we generated soluble monomeric and dimeric peptide–H-2Kb ligands. Soluble monomeric ovalbumin (OVA)-Kb molecules elicited no detectable signaling in OT-I thymocytes, whereas heterodimers of OVA-Kb paired with positively selecting or nonselecting endogenous peptides, but not an engineered null peptide, induced deletion. In contrast, dimer-induced positive selection was much more sensitive to the identity of the partner peptide. Catnb-Kb–Catnb-Kb homodimers, but not heterodimers of Catnb-Kb paired with a nonselecting peptide-Kb, induced positive selection, even though both ligands bind the OT-I TCR with detectable affinity. Thus, both positive and negative selection can be driven by dimeric but not monomeric ligands. In addition, positive selection has much more stringent requirements for the partner self-pMHC.

scholarly journals Different Role of Apaf-1 in Positive Selection, Negative Selection and Death by Neglect in Foetal Thymic Organ Culture

2002 ◽  
Vol 56 (2) ◽  
pp. 174-184 ◽  
Author(s):  
Y. Matsuki ◽  
H.- G. Zhang ◽  
H.- C. Hsu ◽  
P.- A. Yang ◽  
T. Zhou ◽  
...  
Keyword(s):  
Organ Culture ◽  
Positive Selection ◽  
Negative Selection

scholarly journals Revisiting the evolutionary analysis of mammalian CRISPs reveals positive selection

2018 ◽  
Author(s):  
Alberto Vicens ◽  
Claudia Treviño
Keyword(s):  
Positive Selection ◽  
Adaptive Evolution ◽  
Negative Selection ◽  
Secretory Proteins ◽  
Evolutionary Analysis ◽  
Episodic Selection ◽  
Show Evidence ◽  
Selection For ◽  
Related Proteins

AbstractCysteine-rich secretory proteins (CRISPs) constitute a versatile family, with functions that include being components of reptilian venom and participation in mammalian reproduction. While non-mammalian vertebrates express a single CRISP gene, mammals generally express three CRISP paralogs. A previous study assessing the molecular evolution of vertebrate CRISPs revealed strong positive selection in reptilian CRISP and negative selection in mammalian CRISPs. In this study, we re-assessed molecular adaptation of mammalian CRISPs through an analysis of larger sequence datasets that represent mammalian diversity. Our analyses show evidence of recent episodes of positive selection for all mammalian CRISPs. Intensity of positive selection was heterogeneous both among CRISP paralogs (being stronger in CRISP3 than in CRISP1 and CRISP2) and across functional domains (having more impact on CRD or PR-1 domain). Analysis of episodic selection did not yield strong signatures of adaptive evolution in any particular mammalian group, suggesting that positive selection was more pervasive on mammalian CRISPs. Our findings provide evidence of adaptive evolution in a family of reproduction-related proteins, and offer interesting insights regarding the role of mammalian CRISPs in fertility and speciation.

scholarly journals The Selection of M3-Restricted T Cells Is Dependent on M3 Expression and Presentation of N-Formylated Peptides in the Thymus

1999 ◽  
Vol 190 (12) ◽  
pp. 1869-1878 ◽  
Author(s):  
Nancy M. Chiu ◽  
Bin Wang ◽  
Kristen M. Kerksiek ◽  
Roger Kurlander ◽  
Eric G. Pamer ◽  
...  
Keyword(s):  
T Cells ◽  
Negative Selection ◽  
Antigen Processing ◽  
Partial Agonist ◽  
Mhc Class Ib ◽  
Histocompatibility Complex ◽  
Fetal Thymic Organ Culture ◽  
Single Positive ◽  
Class Ib

The major histocompatibility complex (MHC) class Ib molecule H2-M3 binds N-formylated peptides from mitochondria and bacteria. To explore the role of M3 expression and peptide supply in positive and negative selection, we generated transgenic mice expressing an M3-restricted TCR-α/β from a CD8+ T cell hybridoma (D7) specific for a listerial peptide (LemA). Development of M3-restricted transgenic T cells is impaired in both β2-microglobulin–deficient and transporter associated with antigen processing (TAP)-deficient mice, but is not diminished by changes in the H-2 haplotype. Maturation of M3/LemA-specific CD8+ single positive cells in fetal thymic organ culture was sensitive to M3 expression levels as determined by antibody blocking and use of the castaneus mutant allele of M3. Positive selection was rescued in TAP−/− lobes by nonagonist mitochondrial and bacterial peptides, whereas LemA and a partial agonist variant caused negative selection. Thus, M3-restricted CD8+ T cells are positively and negatively selected by M3, with no contribution from the more abundant class Ia molecules. These results demonstrate that class Ib molecules can function in thymic education like class Ia molecules, despite limited ligand diversity and low levels of expression.

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