scholarly journals Specialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Elisabeth H. Vollmann ◽  
Kristin Rattay ◽  
Olga Barreiro ◽  
Aude Thiriot ◽  
Rebecca A. Fuhlbrigge ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Negative Selection ◽  
Blood Stream ◽  
Cell Selection ◽  
Central Tolerance ◽  
Cellular Processes ◽  
Self Tolerance ◽  
Thymic Stroma ◽  
T Cell Selection ◽  
Selection Of

AbstractT cells undergo rigorous selection in the thymus to ensure self-tolerance and prevent autoimmunity, with this process requiring innocuous self-antigens (Ags) to be presented to thymocytes. Self-Ags are either expressed by thymic stroma cells or transported to the thymus from the periphery by migratory dendritic cells (DCs); meanwhile, small blood-borne peptides can access the thymic parenchyma by diffusing across the vascular lining. Here we describe an additional pathway of thymic Ag acquisition that enables circulating antigenic macromolecules to access both murine and human thymi. This pathway depends on a subset of thymus-resident DCs, distinct from both parenchymal and circulating migratory DCs, that are positioned in immediate proximity to thymic microvessels where they extend cellular processes across the endothelial barrier into the blood stream. Transendothelial positioning of DCs depends on DC-expressed CX3CR1 and its endothelial ligand, CX3CL1, and disrupting this chemokine pathway prevents thymic acquisition of circulating proteins and compromises negative selection of Ag-reactive thymocytes. Thus, transendothelial DCs represent a mechanism by which the thymus can actively acquire blood-borne Ags to induce and maintain central tolerance.

scholarly journals RRAS2 shapes the TCR repertoire by setting the threshold for negative selection

2019 ◽  
Vol 216 (10) ◽  
pp. 2427-2447
Author(s):  
Ana Martínez-Riaño ◽  
Elena R. Bovolenta ◽  
Viola L. Boccasavia ◽  
Julia Ponomarenko ◽  
David Abia ◽  
...  
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Cell Selection ◽  
Autoimmune Encephalomyelitis ◽  
Normal Expression ◽  
Tcr Repertoire ◽  
Inflammatory Bowel ◽  
T Cell Selection ◽  
Selection Of ◽  
Experimental Autoimmune

Signal strength controls the outcome of αβ T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2−/− mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE). We show that MOG-specific T cells in Rras2−/− mice have reduced affinity for MOG/I-Ab tetramers, suggesting that enhanced negative selection leads to selection of TCRs with lower affinity for the self-MOG peptide. An analysis of the TCR repertoire shows alterations that mostly affect the TCRα variable (TRAV) locus with specific VJ combinations and CDR3α sequences that are absent in Rras2−/− mice, suggesting their involvement in autoimmunity.

scholarly journals Dormant pathogenic CD4+ T cells are prevalent in the peripheral repertoire of healthy mice

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna Cebula ◽  
Michal Kuczma ◽  
Edyta Szurek ◽  
Maciej Pietrzak ◽  
Natasha Savage ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Receptors ◽  
Negative Selection ◽  
Regulatory Cells ◽  
Central Tolerance ◽  
Therapeutic Advantage ◽  
Autoreactive T Cell ◽  
Peptide Complexes ◽  
Self Peptides

Abstract Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3− T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3+ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4+Foxp3− cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including self-peptides that select them in the thymus. Our data thus suggest that identification of most potentially autoreactive CD4+ T cells in the peripheral repertoire is critical to harness or redirect these cells for therapeutic advantage.

scholarly journals The Action of Bax and Bcl-2 on T Cell Selection

1998 ◽  
Vol 188 (6) ◽  
pp. 1125-1133 ◽  
Author(s):  
Owen Williams ◽  
Trisha Norton ◽  
Mark Halligey ◽  
Dimitris Kioussis ◽  
Hugh J.M. Brady
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Cell Selection ◽  
Direct Role ◽  
Apoptosis Pathway ◽  
Rag 1 ◽  
T Cell Selection

T cell development and selection in the thymus are shaped by the induction of apoptosis. However, a direct role in T cell development and selection for any of the molecules known to regulate apoptosis has remained controversial. We have studied the effect of bax and bcl-2 transgenes in recombination activation gene 1–deficient (RAG-1−/−) mice transgenic for the major histocompatibility complex class I–restricted F5 T cell receptor. Overexpression of a bax transgene in the thymus seriously impairs the production of mature T cells, whereas bcl-2 overexpression greatly promotes it. The effect of bax and bcl-2 overexpression on antigen-induced negative selection was studied using fetal thymic organ cultures. This analysis showed that Bcl-2 strongly inhibits negative selection, whereas Bax does not affect it. Our data directly show that Bcl-2 family members have specific roles in T cell selection and also lend support to the hypothesis that Bax and Bcl-2 can antagonize each other's action in a certain apoptosis pathway while in another they can be functionally nonreciprocal.

In vitro negative selection of viral superantigen-reactive TCR transgenic thymocytes by thymic dendritic cells

1997 ◽  
Vol 56 ◽  
pp. 249
Author(s):  
I. Ferrero ◽  
F. Anjuère ◽  
P. Martin ◽  
H.R. MacDonald ◽  
C. Ardavín
Keyword(s):  
Dendritic Cells ◽  
Negative Selection ◽  
Selection Of

scholarly journals CD1d-expressing Dendritic Cells but Not Thymic Epithelial Cells Can Mediate Negative Selection of NKT Cells

2003 ◽  
Vol 197 (7) ◽  
pp. 907-918 ◽  
Author(s):  
Taehoon Chun ◽  
Michael J. Page ◽  
Laurent Gapin ◽  
Jennifer L. Matsuda ◽  
Honglin Xu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Epithelial Cells ◽  
Negative Selection ◽  
Nkt Cells ◽  
Thymic Epithelial Cells ◽  
High Avidity ◽  
Fetal Thymic Organ Culture ◽  
Self Antigen ◽  
Dose Dependent ◽  
Selection Of

Natural killer T (NKT) cells are a unique immunoregulatory T cell population that is positively selected by CD1d-expressing thymocytes. Previous studies have shown that NKT cells exhibit autoreactivity, which raises the question of whether they are subject to negative selection. Here, we report that the addition of agonist glycolipid α-galactosylceramide (α-GalCer) to a fetal thymic organ culture (FTOC) induces a dose-dependent disappearance of NKT cells, suggesting that NKT cells are susceptible to negative selection. Overexpression of CD1d in transgenic (Tg) mice results in reduced numbers of NKT cells, and the residual NKT cells in CD1d-Tg mice exhibit both an altered Vβ usage and a reduced sensitivity to antigen. Furthermore, bone marrow (BM) chimeras between Tg and WT mice reveal that CD1d-expressing BM-derived dendritic cells, but not thymic epithelial cells, mediate the efficient negative selection of NKT cells. Thus, our data suggest that NKT cells developmentally undergo negative selection when engaged by high-avidity antigen or abundant self-antigen.

scholarly journals Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels

2005 ◽  
Vol 202 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Jens Derbinski ◽  
Jana Gäbler ◽  
Benedikt Brors ◽  
Sascha Tierling ◽  
Sunitha Jonnakuty ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tolerance Induction ◽  
The Body ◽  
Thymic Epithelial Cells ◽  
Peripheral Tissues ◽  
Central Tolerance ◽  
Self Tolerance ◽  
Medullary Thymic Epithelial Cells ◽  
Thymic Stroma

The role of central tolerance induction has recently been revised after the discovery of promiscuous expression of tissue-restricted self-antigens in the thymus. The extent of tissue representation afforded by this mechanism and its cellular and molecular regulation are barely defined. Here we show that medullary thymic epithelial cells (mTECs) are specialized to express a highly diverse set of genes representing essentially all tissues of the body. Most, but not all, of these genes are induced in functionally mature CD80hi mTECs. Although the autoimmune regulator (Aire) is responsible for inducing a large portion of this gene pool, numerous tissue-restricted genes are also up-regulated in mature mTECs in the absence of Aire. Promiscuously expressed genes tend to colocalize in clusters in the genome. Analysis of a particular gene locus revealed expression of clustered genes to be contiguous within such a cluster and to encompass both Aire-dependent and –independent genes. A role for epigenetic regulation is furthermore implied by the selective loss of imprinting of the insulin-like growth factor 2 gene in mTECs. Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance.

scholarly journals Donor Plasmacytoid Dendritic Cells Home to the Thymus of the Transplant Recipient and Limit Graft Versus Host Diseases through Production of Vasoactive Intestinal Polypeptide

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4518-4518
Author(s):  
Yitong Wang ◽  
Yiwen Li ◽  
Jianming Li ◽  
Jingxia Li ◽  
Edmund K. Waller
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Research Funding ◽  
Negative Selection ◽  
Inflammatory Factor ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Selection Of

Abstract Introduction: In allogeneic hematopoietic stem cell transplant (AHSCT), donor T cells promote hematopoietic engraftment, reconstitute T-cell immunity and mediate potent beneficial antitumor effects, such as graft versus leukemia (GVL) as well as detrimental graft-versus-host disease (GVHD). We have shown that purified bone marrow pDC to a donor graft composed of purified HSC and T cells significantly improved long-term leukemia-free survival without increasing the risk of GVHD (Lu BLOOD 2012). Vasoactive intestinal peptide (VIP) is a neuropeptide/neurotransmitter, which acts as a major anti-inflammatory factor in animal models of inflammatory and autoimmune diseases. VIP is produced by T cells and dendritic cells under conditions of inflammation (Li Cancer Research 2016). VIP-signaling, thus represents a newly appreciated co-inhibitory pathway involved in T cell activation and expansion and persistence of antigen-specific T cells, but the role of VIP produced by donor dendritic cells in allo-BMT is unclear. Our previous data has shown that production of VIP in pDC improves survival in a murine allo-BMT model. Since the thymus plays a critical role in regenerating naive T cells in which allo-reactive donor T cells undergoes central deletion. We hypothesized that donor pDCs that home to thymus modulate the negative selection of allo-reactive T cells and iTreg production through VIP signaling. Methods and Results: Our previous data has shown that the mice receiving HSC, T cells and WT pDC had a significantly higher survival (71%) compared to those receiving VIP-KO pDC (31%). On day 15 after transplant, recipients of WT pDC, VIP-KO pDC and no pDC developed ~98% chimerism, without significant differences among the three groups. Local production of VIP in pDC inhibited activation and Th1 immune polarization of donor T cells. Recipient spleens were harvested on day 15 after transplant for analysis of cytokine production by donor T cells. The percentage of CD8+ donor T cells producing IL17 was significantly higher in recipients of VIP-KO pDC compared to recipients of WT-pDC (Fig 2.A-B). The ratio of foxp3+ CD4+ donor T-reg to IL17+ CD4+ T cells from recipients of WT pDC was almost 3 times higher than the recipients of VIP-KO pDC (Fig 2.C-D). To visualize production of VIP by donor pDC, B10.BR mice were transplanted with 5,000 stem cells, 1M T cells and 50,000 pDCs from VIP-GFP (VIP promoter and GFP reporter) or GFP mice. On day 7 post-transplant, the thymus was examined with confocal microscopy with GFP (green), anti-PDCA-1-Alexa Fluor 568 (red) and DAPI (blue). A superimposed profile of the thymus showed that donor GFP pDCs homed to thymus (Fig.2-A), and that donor pDC in the recipient thymus produced VIP (Fig.2-B). Conclusion: Expression of VIP in donor pDCs inhibited activation and Th17 immune polarization of donor CD8+ T cells after allo-BMT. Foxp3+ expression tended to be higher among CD4+ donor T cells from recipients of WT pDCs compared with recipients of VIP-KO pDCs. Thus, VIP-producing donor pDC in thymus could be very critical to contribute to negative selection of allo-reactive donor T cell or facilitate the generation of Foxp3+ nTreg. This data supported a new mechanism by which GvHD maybe regulated and central tolerance maintained. Ongoing experiments aim at defining the role of VIP production in the thymus by donor pDC in positive and negative T cell selection. Disclosures Waller: Celldex: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership; Kalytera: Consultancy; Pharmacyclics: Other: Travel Expenses, EHA, Research Funding.

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