CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment

Hu, Zicheng; Yu, Li; Nieuwenhuijze, Annemarie van; Selden, Hilary J.; Jarrett, Angela M.; Sorace, Anna G.; Yankeelov, Thomas E.; Liston, Adrian; Ehrlich, Lauren I.R.

doi:10.1016/j.celrep.2017.09.016

Cited by 37 publications

(57 citation statements)

References 69 publications

(113 reference statements)

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“…The importance of this is clear from analysis of T cell development in Ccr7 À/À mice [49]. Initially these mice offered a perplexing phenotype: despite exhibiting a severely compromised ability of thymocytes to enter the medulla, the numbers of medulladependent Foxp3 + Tregs were increased relative to wild-type controls [60,61]. Moreover, analysis of Ccr7 À/À /Rag2GFP mice showed that, although de novo development and recent thymic emigrant (RTE) frequency were unaffected, an increase in thymic recirculating Tregs contributed to increased thymic Treg numbers relative to Rag2GFP wild-type controls.…”

Section: Mature Treg Cells In the Thymusmentioning

confidence: 99%

Rethinking Thymic Tolerance: Lessons from Mice

Inglesfield

Cosway

Jenkinson

et al. 2019

Trends in Immunology

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In the thymus, distinct cortex and medulla areas emphasize the division of labor in selection events shaping the abT cell receptor repertoire. For example, MHC restriction via positive selection is a unique property of epithelial cells in the thymic cortex. Far less clear are the events controlling tolerance induction in the medulla. By acting in concert through multiple roles, including antigen production/presentation and chemokine-mediated control of migration, we propose that medullary epithelium and dendritic cells collectively enable the medulla to balance T cell production with negative selection and Foxp3 + regulatory T cell (Treg) development. We examine here the features of these medullary resident cells and their roles in T cell tolerance, and discuss how imbalance in the thymus can result in loss of T cell tolerance. Thymic Medulla and the Control of T Cell ToleranceThe thymus produces multiple T cell types that play key roles in both innate and adaptive immune responses. The importance of these responses has now been shown in sister lineages of vertebrates, long after the function of the thymus was proven for jawed vertebrates in the 1960s [1,2]. Indeed, a key feature of adaptive immunity lies in its ability to generate a wide diversity of antigen receptors that target non-self. For T cells, this is achieved by T cell receptor (TCR) gene rearrangements that take place during T cell development in the thymus. Because of the random nature of gene rearrangement, the thymus imposes stringent mechanisms that shape the abTCR repertoire. Such processes are crucial because they ensure that abT cells (see Glossary) leaving the thymus are not only biased towards the recognition of self-MHC proteins but also tolerant to self-antigens. To achieve this the thymus creates a division of labor: the cortex imposes MHC restriction via positive selection, while the medulla imposes T cell tolerance via a combination of negative selection and Foxp3 + Treg development.The generation of abT cells in the thymus involves immature thymocytes being subjected to sequential checkpoints as they undergo intrathymic migration. To ensure that the thymus produces abT cells capable of antigen recognition in peripheral tissues, the cortex supports positive selection of immature CD4 + CD8 + double-positive (DP) thymocytes that recognize selfpeptide/MHC complexes produced and expressed by cortical thymic epithelial cells (cTECs). This process rescues DP thymocytes from cell death and triggers further differentiation, including expression of the chemokine receptor CCR7 that guides newly selected thymocytes into the medulla [3,4].Because positive selection results in the survival of thymocytes that recognize self-peptide/ MHC, additional selection mechanisms ensure that T cell development produces functional thymocytes that are tolerant to self-antigens. The thymic medulla provides a specialized microenvironment to support these events, and medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) combine to enforce two key proces...

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Section: Mature Treg Cells In the Thymusmentioning

confidence: 99%

Rethinking Thymic Tolerance: Lessons from Mice

Inglesfield

Cosway

Jenkinson

et al. 2019

Trends in Immunology

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“…Various studies have indicated that CCL19 serves a chemotactic role in B cells, dendritic cells and naïve T cells via binding to the C-C motif chemokine receptor (CCR)7 (36)(37)(38). CCR7 is an important antigen molecule expressed on the surface of Treg cells and CCL19 may specifically bind to the receptor CCR7, which in turn exerts chemotactic activity on Treg cells (39)(40)(41). The results of the present study suggested that CCL19 is upregulated in patients with active RA, implying that lncRNA may affect CD4 + T lymphocytes by regulating mRNA-CCL19, which in turn affects the differentiation of cells.…”

Section: Discussionmentioning

confidence: 99%

Differential long non‑coding RNA expression profiles in the peripheral blood and CD4+ T cells of patients with active rheumatoid arthritis

Feng

et al. 2020

Exp Ther Med

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The human transcriptome is primarily composed of long non-coding RNAs (lncRNAs), which are key regulatory molecules of multiple biological processes. In the present study, the expression profiles of lncRNAs in the peripheral blood and CD4 + T cells of patients with active rheumatoid arthritis (RA) were determined. Based on the expression profiles, 493 lncRNAs and 374 mRNAs were identified to be differentially expressed in the peripheral blood of active RA patients and healthy donors. Further verification of lncRNAs was performed using reverse transcription-quantitative (RT-q) PCR analysis of peripheral blood from 5 healthy donors and 5 patients with active RA and 14 additional differentially expressed genes were identified. CD4 + T cells in peripheral blood from 12 patients with active RA and 8 healthy donors were isolated using magnetic beads and qPCR was used to assess differentially expressed lncRNAs. The results suggested that 7 lncRNAs were upregulated and 2 were downregulated. The results indicated that these 9 lncRNAs may be involved in the pathogenesis of RA. An increased ratio of Th17: T-regulatory (Treg) cells was also observed. It may be hypothesized that LncRNAs serve important roles in the differentiation of CD4 + T cells. Receiver operating characteristic curve analysis suggested that these 9 lncRNAs are of potential clinical diagnostic value for RA. Pearson correlation analysis indicated that the correlation coefficient between Ensembl transcript (ENST)00000569543 and complement C4 was 0.623 (P<0.05), and that between ENST00000420096 and anti-cyclic citrullinated peptide antibody or disease activity evaluation score, the correlation coefficient was 0.662 and 0.605, respectively (P<0.05 for each). In conclusion, the results of the present study suggest a possible role of lncRNAs in the differentiation of CD4 + T cells and the pathogenesis of RA, as well as the potential value as diagnostic biomarkers for active RA.

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“…Quantification of cortical and medullary areas from immunofluorescent slide images was done using an automated MATLAB (Mathworks, Natick, MA) code to calculate the areas of medullary regions, cortical regions, and overlap as previously described [ 34 ]. Briefly, the two color channels were first identified, and two new regions were created to determine non-overlapping regions for strictly medullary or strictly cortical areas.…”

Section: Methodsmentioning

confidence: 99%

CCR8 is expressed by post-positive selection CD4-lineage thymocytes but is dispensable for central tolerance induction

Thyagarajan¹,

Lancaster²,

Lira³

et al. 2018

PLoS ONE

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Following positive selection, thymocytes migrate into the medulla where they encounter diverse self-antigens that induce central tolerance. Thymocytes expressing T cell receptors (TCRs) with high affinity for self-antigens displayed by medullary antigen presenting cells (APCs) undergo either negative selection or diversion to the regulatory T cell (Treg) lineage, thus ensuring maturation of non-autoreactive T cells. Because many self-antigens are expressed by only a small percentage of medullary thymic epithelial cells, thymocytes must enter the medulla and efficiently scan APCs therein to encounter the full array of self-antigens that induce central tolerance. Chemokine receptors play a critical role in promoting medullary entry and rapid motility of post-positive selection thymocytes. We found that the chemokine receptor CCR8 is expressed by post-positive selection CD4+ single positive (SP) thymocytes in mice, while the corresponding chemokine ligands are expressed by medullary APCs, and thus hypothesized that CCR8 would promote thymocyte medullary entry and/or rapid motility to induce negative selection. However, despite a subtle decline in thymocyte medullary accumulation and the presence of autoantibodies in aged CCR8-deficient mice, CCR8 was not required for thymocyte differentiation, rapid motility, or negative selection.

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CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment

Cited by 37 publications

References 69 publications

Rethinking Thymic Tolerance: Lessons from Mice

Rethinking Thymic Tolerance: Lessons from Mice

Differential long non‑coding RNA expression profiles in the peripheral blood and CD4+ T cells of patients with active rheumatoid arthritis

CCR8 is expressed by post-positive selection CD4-lineage thymocytes but is dispensable for central tolerance induction

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