Temporal increase in thymocyte negative selection parallels enhanced thymic SIRPα<sup>+</sup> DC function

Kroger, Charles J.; Wang, Bo; Tisch, Roland

doi:10.1002/eji.201646354

Cited by 17 publications

(18 citation statements)

References 48 publications

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“…Interestingly, although thymic DCs regulate both negative selection and T-reg development, DC defects in Ltbr −/− mice correlate with a selective reduction in thymocytes undergoing negative selection. This emphasizes the importance of DC-mediated negative selection as a mechanism of thymic tolerance, which is in agreement with a quantitative requirement for DCs in thymocyte deletion ( Anderson et al, 1998 ; Kroger et al, 2016 ). Moreover, although mTECs influence thymic DCs ( Lei et al, 2011 ; Spidale et al, 2014 ), the role of LTβR in formation of the thymic DC pool maps to non-TEC stroma.…”

Section: Resultssupporting

confidence: 69%

Redefining thymus medulla specialization for central tolerance

Cosway

Lucas

James

et al. 2017

Journal of Experimental Medicine

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Section: Resultssupporting

confidence: 69%

Redefining thymus medulla specialization for central tolerance

Cosway

Lucas

James

et al. 2017

Journal of Experimental Medicine

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“…Whether the reduced peripheral T‐Reg numbers in the thymus of Aire −/− mice are still able to effectively compete for IL‐2 and limit new T‐Reg production is not clear. Interestingly, CCL20 directs CCR6 + T‐Reg to peripheral inflammatory sites , and its expression by mTEC for the attraction of CCR6 + T‐Reg correlates with conditions within medullary thymic microenvironments that support constitutive MHC class II expression and elevated co‐stimulatory molecules on thymic APC . Whether recirculating T‐Reg influence the thymic medullary microenvironments they reside within is currently not known.…”

Section: Discussionmentioning

confidence: 99%

Aire controls the recirculation of murine Foxp3⁺ regulatory T‐cells back to the thymus

et al. 2018

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In the thymus, medullary thymic epithelial cells (mTEC) determine the fate of newly selected CD4+ and CD8+ single positive (SP) thymocytes. For example, mTEC expression of Aire controls intrathymic self‐antigen availability for negative selection. Interestingly, alterations in both Foxp3+ Regulatory T‐cells (T‐Reg) and conventional SP thymocytes in Aire−/− mice suggest additional, yet poorly understood, roles for Aire during intrathymic T‐cell development. To examine this, we analysed thymocytes from Aire −/− mice using Rag2GFP and Foxp3 expression, and a recently described CD69/MHCI subset definition of post‐selection CD4+ conventional thymocytes. We show that while Aire is dispensable for de novo generation of conventional αβT‐cells, it plays a key role in controlling the intrathymic T‐Reg pool. Surprisingly, a decline in intrathymic T‐Reg in Aire−/− mice maps to a reduction in mature recirculating Rag2GFP− T‐Reg that express CCR6 and re‐enter the thymus from the periphery. Furthermore, we show mTEC expression of the CCR6 ligand CCL20 is reduced in Aire−/− mice, and that CCR6 is required for T‐Reg recirculation back to the thymus. Collectively, our study re‐defines requirements for late stage intrathymic αβT‐cell development, and demonstrates that Aire controls a CCR6‐CCL20 axis that determines the developmental makeup of the intrathymic T‐Reg pool.

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“…Considering this, a recent study [36] reported a reduced ability of newborn non-obese diabetic (NOD) mice to support peptide-induced thymocyte deletion compared to 4 week old mice; this impairment in thymocyte deletion correlated with thymic DC alterations, in particular for cDC2 cells [36]. Thus, balance between differing thymic DC subsets may be necessary for optimal tolerance during thymocyte development.…”

Section: Regulation Of Intrathymic Dcsmentioning

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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Temporal increase in thymocyte negative selection parallels enhanced thymic SIRPα⁺ DC function

Cited by 17 publications

References 48 publications

Redefining thymus medulla specialization for central tolerance

Redefining thymus medulla specialization for central tolerance

Aire controls the recirculation of murine Foxp3⁺ regulatory T‐cells back to the thymus

Rethinking Thymic Tolerance: Lessons from Mice

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Temporal increase in thymocyte negative selection parallels enhanced thymic SIRPα+ DC function

Cited by 17 publications

References 48 publications

Redefining thymus medulla specialization for central tolerance

Redefining thymus medulla specialization for central tolerance

Aire controls the recirculation of murine Foxp3+ regulatory T‐cells back to the thymus

Rethinking Thymic Tolerance: Lessons from Mice

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Temporal increase in thymocyte negative selection parallels enhanced thymic SIRPα⁺ DC function

Aire controls the recirculation of murine Foxp3⁺ regulatory T‐cells back to the thymus