Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A role for phagocytosis in inducing cell death during thymocyte negative selection.

ABSTRACT: Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, using a murine thymic slice model in which thymocytes undergo negative selection in situ, we demonstrate that phagocytosis promotes negative selection, and provide evidence for the escape of autoreactive CD8 T cells to the periphery when phagocytosis in the thymus is impaired. We also show that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a model for negative selection in which the death process initiated following strong TCR signaling is facilitated by phagocytosis. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.

SUBMITTER: Kurd NS

PROVIDER: S-EPMC6957271 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A role for phagocytosis in inducing cell death during thymocyte negative selection.

Kurd Nadia S NS Lutes Lydia K LK Yoon Jaewon J Chan Shiao Wei SW Dzhagalov Ivan L IL Hoover Ashley R AR Robey Ellen A EA

eLife 20191223

Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, using a murine thymic slice model in which thymocytes undergo negative selection in situ, we demonstrate that phagocytosis promotes negative selection, and provide evidence for the escape of autoreactive CD8 T cells to the perip ...[more]

PMID: 31868579

Similar Datasets

Thymocyte Negative Selection

Project description:Fetal thymic organ culture (FTOC) DC2.5 CD4+CD8+ thymocytes from B6g7 or NOD background. 0 or 16 hour after addition of the BDC mimitope Keywords = BDC2.5 FTOC thymocyte Keywords: dose response

2005-04-05 | GSE2128 | GEO

Crossreactive ?? T Cell Receptors Are the Predominant Targets of Thymocyte Negative Selection.

Project description:The precise impact of thymic positive and negative selection on the T cell receptor (TCR) repertoire remains controversial. Here, we used unbiased, high-throughput cloning and retroviral expression of individual pre-selection TCRs to provide a direct assessment of these processes at the clonal level in vivo. We found that 15% of random TCRs induced signaling and directed positive (7.5%) or negative (7.5%) selection, depending on strength of signal, whereas the remaining 85% failed to induce signaling or selection. Most negatively selected TCRs exhibited promiscuous crossreactivity toward multiple other major histocompatibility complex (MHC) haplotypes. In contrast, TCRs that were positively selected or non-selected were minimally crossreactive. Negative selection of crossreactive TCRs led to clonal deletion but also recycling into intestinal CD4(-)CD8?(-) intraepithelial lymphocytes (iIELs). Thus, broadly crossreactive TCRs arise at low frequency in the pre-selection repertoire but constitute the primary drivers of thymic negative selection and iIEL lineage differentiation.

| S-EPMC4654978 | biostudies-literature

CBAP promotes thymocyte negative selection by facilitating T-cell receptor proximal signaling.

Project description:T-cell receptor (TCR)-transduced signaling is critical to thymocyte development at the CD4/CD8 double-positive stage, but the molecules involved in this process are not yet fully characterized. We previously demonstrated that GM-CSF/IL-3/IL-5 receptor common ?-chain-associated protein (CBAP) modulates ZAP70-mediated T-cell migration and adhesion. On the basis of the high expression of CBAP during thymocyte development, we investigated the function of CBAP in thymocyte development using a CBAP knockout mouse. CBAP-deficient mice showed normal early thymocyte development and positive selection. In contrast, several negative selection models (including TCR transgene, superantigen staphylococcal enterotoxin B, and anti-CD3 antibody treatment) revealed an attenuation of TCR-induced thymocyte deletion in CBAP knockout mice. This phenotype correlated with a reduced accumulation of BIM upon TCR crosslinking in CBAP-deficient thymocytes. Loss of CBAP led to reduced TCR-induced phosphorylation of proteins involved in both proximal and distal signaling events, including ZAP70, LAT, PLC?1, and JNK1/2. Moreover, TCR-induced association of LAT signalosome components was reduced in CBAP-deficient thymocytes. Our data demonstrate that CBAP is a novel component in the TCR signaling pathway and modulates thymocyte apoptosis during negative selection.

| S-EPMC4260732 | biostudies-literature

Stable interactions and sustained TCR signaling characterize thymocyte-thymocyte interactions that support negative selection.

Project description:Negative selection is one of the primary mechanisms that render T cells tolerant to self. Thymic dendritic cells play an important role in negative selection, in line with their ability to induce migratory arrest and sustained TCR signals. Thymocytes themselves display self-peptide/MHC class I complexes, and although there is evidence that they can support clonal deletion, it is not clear whether they do so directly via stable cell-cell contacts and sustained TCR signals. In this study, we show that murine thymocytes can support surprisingly efficient negative selection of Ag-specific thymocytes. Furthermore, we observe that agonist-dependent thymocyte-thymocyte interactions occurred as stable, motile conjugates led by the peptide-presenting thymocyte and in which the trailing peptide-specific thymocyte exhibited persistent elevations in intracellular calcium concentration. These data confirm that self-Ag presentation by thymocytes is an additional mechanism to ensure T cell tolerance and further strengthen the correlation between stable cellular contacts, sustained TCR signals, and efficient negative selection.

| S-EPMC4297692 | biostudies-literature

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection.

Project description:The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit ? (Ppp2ca) deletion in the T cell lineage in Ppp2ca flox/flox-Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4+ CD8+ cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival.

| S-EPMC6589683 | biostudies-literature

Glucocorticoids Oppose Thymocyte Negative Selection by Inhibiting Helios and Nur77.

Project description:Glucocorticoid (GC) signaling in thymocytes shapes the TCR repertoire by antagonizing thymocyte negative selection. The transcription factors Nur77 and Helios, which are upregulated in TCR-signaled thymocytes, have been implicated in negative selection. In this study, we found that GCs inhibited Helios and, to a lesser extent, Nur77 upregulation in TCR-stimulated mouse thymocytes. Inhibition was increased by GC preincubation, and reductions in mRNA were prevented by a protein synthesis inhibitor, suggesting that GCs suppress indirectly via an intermediary factor. Upregulation of Helios in TCR-stimulated thymocytes was unaffected by deletion of Nur77, indicating Nur77 and Helios are regulated independently. Whereas CD4+ thymocytes are positively selected in wild-type AND TCR-transgenic B6 mice, loss of GC receptor expression resulted in increased negative selection. Correspondingly, Helios and Nur77 levels were elevated in TCRhiCD4+CD8+ (TCR-signaled) thymocytes. Notably, deletion of Helios fully reversed this negative selection, whereas deletion of Nur77 had no effect on CD4+CD8+ cell numbers but reversed the loss of mature CD4+ thymocytes. Thus, Nur77 and Helios are GC targets that play nonredundant roles in setting the signaling threshold for thymocyte negative selection.

| S-EPMC6783372 | biostudies-literature

Pre-T cell receptors topologically sample self-ligands during thymocyte β-selection.

Project description:Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre-T cell receptors (preTCRs) and αβTCRs. Using x-ray crystallography, we show how a preTCR applies the concave β-sheet surface of its single variable domain (Vβ) to "horizontally" grab the protruding MHC α2-helix. By contrast, αβTCRs purpose all six complementarity-determining region (CDR) loops of their paired VαVβ module to recognize peptides bound to major histocompatibility complex molecules (pMHCs) in "vertical" head-to-head binding. The preTCR topological fit ensures that CDR3β reaches the peptide's featured C-terminal segment for pMHC sampling, establishing the subsequent αβTCR canonical docking mode. "Horizontal" docking precludes germline CDR1β- and CDR2β-MHC binding to broaden β-chain repertoire diversification before αβTCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.

| S-EPMC8011828 | biostudies-literature

The impact of negative selection on thymocyte migration in the medulla.

Project description:Developing thymocytes are screened for self-reactivity before they exit the thymus, but how thymocytes scan the medulla for self antigens is unclear. Using two-photon microscopy, we observed that medullary thymocytes migrated rapidly and made frequent, transient contacts with dendritic cells. In the presence of a negative selecting ligand, thymocytes slowed, became confined to areas of approximately 30 microm in diameter and had increased contact with dendritic cells surrounding confinement zones. One third of polyclonal medullary thymocytes also showed confined, slower migration and may correspond to autoreactive thymocytes. Our data suggest that many autoreactive thymocytes do not undergo immediate arrest and death after encountering a negative selecting ligand but instead adopt an altered migration program while remaining in the medullary microenvironment.

| S-EPMC2793676 | biostudies-literature

Temporal increase in thymocyte negative selection parallels enhanced thymic SIRP?+ DC function.

Project description:Dysregulation of negative selection contributes to T-cell-mediated autoimmunity, such as type 1 diabetes. The events regulating thymic negative selection, however, are ill defined. Work by our group and others suggest that negative selection is inefficient early in ontogeny and increases with age. This study examines temporal changes in negative selection and the thymic DC compartment. Peptide-induced thymocyte deletion in vivo was reduced in newborn versus 4-week-old NOD mice, despite a similar sensitivity of the respective thymocytes to apoptosis induction. The temporal increase in negative selection corresponded with an elevated capacity of thymic antigen-presenting cells to stimulate T cells, along with altered subset composition and function of resident DC. The frequency of signal regulatory protein ?+ (SIRP?+ ) and plasmacytoid DCs was increased concomitant with a decrease in CD8?+ DC in 4-week-old NOD thymi. Importantly, 4-week-old versus newborn thymic SIRP?+ DC exhibited increased antigen processing and presentation via the MHC class II but not class I pathway, coupled with an enhanced T-cell stimulatory capacity not seen in thymic plasmacytoid DC and CD8?+ DC. These findings indicate that the efficiency of thymic DC-mediated negative selection is limited early after birth, and increases with age paralleling expansion of functionally superior thymic SIRP?+ DC.

| S-EPMC5138854 | biostudies-literature

CD6 modulates thymocyte selection and peripheral T cell homeostasis.

Project description:The CD6 glycoprotein is a lymphocyte surface receptor putatively involved in T cell development and activation. CD6 facilitates adhesion between T cells and antigen-presenting cells through its interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), and physically associates with the T cell receptor (TCR) at the center of the immunological synapse. However, its precise role during thymocyte development and peripheral T cell immune responses remains to be defined. Here, we analyze the in vivo consequences of CD6 deficiency. CD6(-/-) thymi showed a reduction in both CD4(+) and CD8(+) single-positive subsets, and double-positive thymocytes exhibited increased Ca(2+) mobilization to TCR cross-linking in vitro. Bone marrow chimera experiments revealed a T cell-autonomous selective disadvantage of CD6(-/-) T cells during development. The analysis of TCR-transgenic mice (OT-I and Marilyn) confirmed that abnormal T cell selection events occur in the absence of CD6. CD6(-/-) mice displayed increased frequencies of antigen-experienced peripheral T cells generated under certain levels of TCR signal strength or co-stimulation, such as effector/memory (CD4(+)TEM and CD8(+)TCM) and regulatory (T reg) T cells. The suppressive activity of CD6(-/-) T reg cells was diminished, and CD6(-/-) mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and/or function of several peripheral T cell subpopulations, including T reg cells.

| S-EPMC4986531 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data