CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance

Hu, Zicheng; Lancaster, Jessica N.; Sasiponganan, Chayanit; Ehrlich, Lauren I.R.

doi:10.1084/jem.20150178

Cited by 70 publications

(97 citation statements)

References 64 publications

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“…However, neither MHCII nor co-stimulatory molecules are expressed at high levels on immature Sirpα + DC (data not shown). Another possibility is that Sirpα + DC express high levels of CCR4 ligands (Hu et al, 2015b; Proietto et al, 2008). We previously reported that CCR4 expression on immature CD4SP thymocytes is required for efficient interactions with medullary DC (Hu et al, 2015b).…”

Section: Discussionmentioning

confidence: 99%

“…Another possibility is that Sirpα + DC express high levels of CCR4 ligands (Hu et al, 2015b; Proietto et al, 2008). We previously reported that CCR4 expression on immature CD4SP thymocytes is required for efficient interactions with medullary DC (Hu et al, 2015b). Thus, MHCII lo Sirpα + DC could induce Treg efficiently because of avid interactions with early-post positive selection thymocytes.…”

Section: Discussionmentioning

confidence: 99%

“…After positive selection, thymocytes differentiate into CD4 + single positive (CD4SP) or CD8 + single positive (CD8SP) cells and upregulate the chemokine receptors CCR4 and CCR7 to guide them from the cortex into the medulla (Cowan et al, 2014; Hu et al, 2015a, 2015b). The thymic medulla is enriched for antigen presenting cells (APC) that display numerous self-antigens to tolerize autoreactive thymocytes.…”

Section: Introductionmentioning

confidence: 99%

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

Nieuwenhuijze

et al. 2017

Cell Reports

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Summary Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory T cell (Treg) fate. CCR7 is required for negative selection of auto-reactive thymocytes in the thymic medulla. Here we describe an unanticipated contribution of CCR7 to intrathymic Treg generation. Ccr7−/− mice have increased Treg cellularity, due to a hematopoietic, but non-T cell autonomous CCR7 function. CCR7 expression by thymic dendritic cells (DC) promotes survival of mature Sirpα− DC. Thus, CCR7 deficiency results in apoptosis of Sirpα− DC, which is counterbalanced by expansion of immature Sirpα+ DC, which efficiently induce Treg generation. CCR7 deficiency results in enhanced intrathymic generation of Treg at the neonatal stage and in lymphopenic adults, when Treg differentiation is critical for establishing self-tolerance. Together these results reveal a complex function for CCR7 in thymic tolerance induction, in which CCR7 not only promotes negative selection, but also governs intrathymic Treg generation via non-thymocyte intrinsic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nieuwenhuijze

et al. 2017

Cell Reports

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“…More recently, it was shown that DCs are not simply bystanders in the thymocyte selection process. They actively attract post-positive selection thymocytes by producing CCR4 ligand to facilitate the negative selection process (28). Interestingly, and likely due to the experimental challenges associated with separating central and peripheral tolerance processes, the general outcome of a defect in DC-mediated central tolerance on the potential development of an autoimmune phenotype has yet to be clearly defined.…”

Section: Thymic Tolerancementioning

confidence: 99%

The Importance of Dendritic Cells in Maintaining Immune Tolerance

Audiger

Rahman

Yun

et al. 2017

The Journal of Immunology

222

160

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Immune tolerance is necessary to prevent the immune system from reacting against self, and thus to avoid the development of autoimmune diseases. Here, we review key findings that position dendritic cells (DCs) as critical modulators of both thymic and peripheral immune tolerance. Although DCs are important for inducing both immunity and tolerance, increased autoimmunity associated with decreased DCs suggests their non-redundant role in tolerance induction. DC-mediated T cell immune tolerance is an active process that is influenced by genetic variants, environmental signals as well as the nature of the specific DC subset presenting antigen to T cells. Answering the many open questions with regards to the role of DC in immune tolerance could lead to the development of novel therapies for the prevention of autoimmune diseases.

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“…More recently, SP thymocyte heterogeneity has further been revealed using a variety of additional cell surface phenotypes, including the chemokine receptors CCR4, CCR7, and CCR9. Using this approach to analyze CD4 + SP thymocyte developmental heterogeneity, expression of CCR4 and CCR9 was shown to identify newly generated cells, with more mature cells having a CCR4 − CCR7 + CCR9 − phenotype . Additional phenotypic markers used to separate SP thymocytes on the basis of their developmental status include CD69, CD62L, and Qa2, although the relevance of expression levels of the latter in relation to maturational state has recently been questioned .…”

Section: Regulators Of Thymus Emigrationmentioning

confidence: 99%

T-cell egress from the thymus: Should I stay or should I go?

James

Jenkinson

Anderson

2018

Journal of Leukocyte Biology

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T‐cells bearing the αβTCR play a vital role in defending the host against foreign pathogens and malignant transformation of self. Importantly, T‐cells are required to remain tolerant to the host's own cells and tissues in order to prevent self‐reactive responses that can lead to autoimmune disease. T‐cells achieve the capacity for self/nonself discrimination by undergoing a highly selective and rigorous developmental program during their maturation in the thymus. This organ is unique in its ability to support a program of T‐cell development that ensures the establishment of a functionally diverse αβTCR repertoire within the peripheral T‐cell pool. The thymus achieves this by virtue of specialized stromal microenvironments that contain heterogeneous cell types, whose organization and function underpins their ability to educate, support, and screen different thymocyte subsets through various stages of development. These stages range from the entry of early T‐cell progenitors into the thymus, through to the positive and negative selection of the αβTCR repertoire. The importance of the thymus medulla as a site for T‐cell tolerance and the exit of newly generated T‐cells into the periphery is well established. In this review, we summarize current knowledge on the developmental pathways that take place during αβT‐cell development in the thymus. In addition, we focus on the mechanisms that regulate thymic egress and contribute to the seeding of peripheral tissues with newly selected self‐tolerant αβT‐cells.

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CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance

Abstract: Hu et al. show that the chemokine receptor CCR4 is involved in thymocyte medullary entry, interactions with dendritic cells, and negative selection. In the absence of CCR4, central tolerance is not established, promoting autoimmunity.

Cited by 70 publications

References 64 publications

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

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

The Importance of Dendritic Cells in Maintaining Immune Tolerance

T-cell egress from the thymus: Should I stay or should I go?

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