Thymic Crosstalk Coordinates Medulla Organization and T-Cell Tolerance Induction

Lopes, Noëlla; Sergé, Arnauld; Ferrier, Pierre; Irla, Magali

doi:10.3389/fimmu.2015.00365

Cited by 75 publications

(82 citation statements)

References 122 publications

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“…The lack of overt autoimmunity in Traf6ΔTEC mice (despite the depletion of mTECs and reduction in tTregs) suggested that compensatory mechanisms might operate to suppress inflammation in these mice. Indeed, previous evidence supports functional cooperation among the different thymic APC populations relating to autoreactive T cell deletion and tTreg cell production [reviewed by [20]]. Migratory SIRPα + cDCs were shown to regulate T cell deletion and were potent inducers of tTreg cell production [5, 6, 21] whereas plasmacytoid DCs (pDCs) primarily regulate tolerance through T cell deletion [8].…”

Section: Resultsmentioning

confidence: 99%

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Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Herbin

Bonito

Jeong

et al. 2016

Journal of Autoimmunity

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In the thymus, antigen presenting cells (APCs) namely, medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) regulate T cell tolerance through elimination of autoreactive T cells and production of thymic T regulatory (tTreg) cells. How the different APCs in the thymus share the burden of tolerazing the emerging T cell repertoire remains unclear. For example, while mutations that inhibit mTEC development or function associate with peripheral autoimmunity, the role of tDCs in organ-specific autoimmunity and tTreg cell production remains controversial. In this report we used mice depleted of mTECs and/or CD8α+ DCs, to examine the contributions of these cell populations in thymic tolerance. We found that while mice depleted of CD8α+ DCs or mTECs were normal or developed liver inflammation respectively, combined depletion of mTECs and CD8α+ DCs resulted in overt peripheral autoimmunity. The autoimmune manifestations in mice depleted of both mTECs and CD8α+ cDCs associated with increased percentages of CD4+ and CD8+ T cells in the thymus. In contrast, while mTEC depletion resulted in reduced percentages of tTreg cells, no additional effect was observed when CD8α+ DCs were also depleted. These results reveal that: 1) mTECs and CD8α+ DCs cooperatively safeguard against peripheral autoimmunity through thymic T cell deletion; 2) CD8α+ DCs are dispensable for tTreg cell production, whereas mTECs play a non-redundant role in this process; 3) mTECs and CD8α+ DCs make unique contributions to tolerance induction that cannot be compensated for by other thymic APCs such as migratory SIRPα+ or plasmacytoid DCs.

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Section: Resultsmentioning

confidence: 99%

“…Previous evidence has shown functional cooperation among the different thymic APC populations relating to autoreactive T cell deletion [reviewed by [20]]. Deletion of autoreactive T cells can be mediated by mTECs in a cell autonomous fashion as well as by all thymic DC populations.…”

Section: Resultsmentioning

confidence: 99%

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Herbin

Bonito

Jeong

et al. 2016

Journal of Autoimmunity

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“…The thymic medullae are integrated by DC and mTEC that create a microenvironment conducive to induce T-cell tolerance. The mTEC express a wide repertoire of tissue-restricted self-antigens (TRA) that granted these cells the leadership in the induction of cell tolerance (Lopes et al 2015). DC are also relevant for the negative selection of immature T-cells (Oh & Shin 2015); previous studies in mice from our group demonstrated that V inhalation decreased the number of DC as well as expression of CD11c -a DC biomarker (Ustarroz-Cano et al 2012).…”

Section: Cells Take Place the Dp T-cells Return To The Medulla To Bementioning

confidence: 99%

Thymic cytoarchitecture changes in mice exposed to vanadium

Ustarroz-Cano¹,

García-Peláez²,

Cervantes-Yépez³

et al. 2017

Journal of Immunotoxicology

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The thymus is a vital immune system organ wherein selection of T-lymphocytes occurs in a process regulated by dendritic and epithelial thymic cells. Previously, we have reported that in a mouse model of vanadium inhalation, a decrease in CD11c dendritic cells was observed. In the present study, we report on a thymic cortex-medulla distribution distortion in these hosts due to apparent effects of the inhaled vanadium on cytokeratin-5 (K5 þ ) epithelial cells in the same mouse model -after 1, 2, and 4 weeks of exposure -by immunohistochemistry. These cells -together with dendritic cells -eliminate autoreactive T-cell clones and regulate the production of regulatory T-cells in situ. Because both cell types are involved in the negative selection of autoreactive clones, a potential for an increase in development of autoimmune conditions could be a possible consequence among individuals who might be exposed often to vanadium in air pollution, including dwellers of highly polluted cities with elevated levels of particulate matter onto which vanadium is often adsorbed. ARTICLE HISTORY

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“…Later in ontogeny, mTECs can develop from cTEC-like precursors 10 , indicating a concurrent upregulation of mTEC genes and downregulation of cTEC-specific genes at this developmental transition. TEC differentiation and maturation are highly dependent on bi-directional signaling between developing T-cells and TECs in a process termed thymic crosstalk 11 . mTEC emergence and maturation at E16 is regulated by RANK (Receptor Activator of Nuclear Factor κ B) ligand (RANKL)-expressing innate-like lymphoid cells (ILCs) 12 and Vγ5 dendritic epidermal T-cells (DETCs) 13 .…”

Section: Introductionmentioning

confidence: 99%

A key role for IL‐7R in the generation of microenvironments required for thymic dendritic cells

Moore

Trotman-Grant

et al. 2017

Immunol Cell Biol

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Interleukin-7 receptor (IL-7R) signaling is critical for multiple stages of T-cell development, but a role in the establishment of the mature thymic architecture needed for T-cell development and thymocyte selection has not been established. Crosstalk signals between developing thymocytes and thymic epithelial cell (TEC) precursors are critical for their differentiation into cortical TECs (cTECs) and medullary TECs (mTECs). Additionally, mTECs-derived factors have been implicated in the recruitment of thymic dendritic cells (DCs) and intrathymic DC development. We therefore examined corticomedullary structure and DC populations in the thymus of Il7r−/− mice. Analysis of TEC phenotype and spatial organization revealed a striking shift in the mTEC to cTEC ratio, accompanied by disorganized corticomedullary structure. Several of the thymic subsets known to have DC potential were nearly absent, accompanied by reductions in DC cell numbers. We also examined chemokine expression in the Il7r−/− thymus, and found a significant decrease in mTEC-derived CCR7 ligand expression, and high levels of cTEC-derived chemokines, including CCL25 and CXCL12. Although splenic DCs were similarly affected, bone marrow precursors capable of giving rise to DCs were unperturbed. Finally, bone marrow chimeras showed that there was no intrinsic need for IL-7R signaling in the development or recruitment of thymic DCs, but that the provision of WT progenitors enhanced reconstitution of thymic DCs from Il7r−/− progenitors. Our results are therefore supportive of a model in which Il7r-dependent cells are required to set up the microenvironments that allow accumulation of thymic DCs.

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Thymic Crosstalk Coordinates Medulla Organization and T-Cell Tolerance Induction

Cited by 75 publications

References 122 publications

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Thymic cytoarchitecture changes in mice exposed to vanadium

A key role for IL‐7R in the generation of microenvironments required for thymic dendritic cells

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