A type 2 cytokine axis for thymus emigration

White, Andrea J.; Baik, Song; Parnell, Sonia M.; Holland, Aliya; Brombacher, Frank; Jenkinson, William E.; Anderson, Graham

doi:10.1084/jem.20170271

Cited by 37 publications

(57 citation statements)

References 53 publications

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“…Although the functional significance of this retention is unclear, it is interesting that CD1drestricted iNKT cells can also reside in the thymus for long periods, where they can influence T cell development, including thymic export [54,55]. However, the relative contributions that thymic recirculation and retention make to modulate the presence of mature Tregs in the thymus remains unclear.…”

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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“…To examine the detailed changes in IL‐4 and IL‐4R alpha mRNA expression that occur following SNI, we performed RT‐PCR using total RNA extracted from the dorsal ipsilateral L4/5 segment of the spinal cord. Thymus tissue was used as a positive control for IL‐4 and IL‐4R (White et al, ). Primer sets that amplified IL‐4 mRNA in the thymus did not detect the expression of IL‐4 mRNA in the dorsal horn (Figure a,c) and dorsal root ganglion in the naïve control or SNI groups (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Thymus tissue was used as a positive control for IL-4 and IL-4R (White et al, 2017). Primer sets that amplified IL-4 mRNA in the thymus did not detect the expression of IL-4 mRNA in the dorsal horn (Figure 1a,c) and dorsal root ganglion in the naïve control or SNI groups (data not shown).…”

Section: Peripheral Nerve Injury Upregulates Il-4r Alpha Expressionmentioning

confidence: 96%

Recombinant interleukin‐4 alleviates mechanical allodynia via injury‐induced interleukin‐4 receptor alpha in spinal microglia in a rat model of neuropathic pain

Okutani

Yamanaka

Kobayashi

et al. 2018

Glia

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Glial cells play important roles in the development and maintenance of neuropathic pain. In particular, activated microglia in the spinal cord facilitate the hyper-excitability of dorsal horn neurons after peripheral nerve injury via pro-inflammatory molecules. In this study, we investigated the possible involvement of the anti-inflammatory cytokine, interleukin-4 (IL-4), in neuropathic pain. We did not detect the expression of IL-4 mRNA in the rat dorsal root ganglion or spinal cord; however, peripheral nerve injury induced the expression of IL-4 receptor (IL-4R) alpha mRNA in the spinal cord. A histological analysis revealed that nerve injury induced IL-4R alpha mRNA in activated spinal microglia ipsilateral to the injury site. Additionally, the increases in IL-4R alpha were coincident with the increased expression of phosphorylated signal transducer and activator of transcription 6 (pSTAT6) in spinal microglia. Intrathecal administration of recombinant IL-4 suppressed mechanical hypersensitivity in neuropathic rats, and the analgesic effect of IL-4 was accompanied by further enhancement of pSTAT6 expression in spinal microglia. Taken together, these results suggest that the adaptive responses of microglia to nerve injury involve both inflammatory and anti-inflammatory signaling, including IL-4R alpha and pSTAT6. These findings support that utilizing the endogenous anti-nociceptive activity of IL-4R alpha may modify the cell lineage of pro-nociceptive microglia, thus providing a novel therapeutic strategy for neuropathic pain.

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“…Specifically, we investigated the intrathymic positioning of mature SP4 and SP8 thymocytes, and concentrated on mouse strains where the typical random distribution of these cells within thymic medullary areas was altered. We saw that in Il4ra −/− mice, the thymus medulla contained large mTEC‐free areas filled with SP thymocytes, and the thymus was enriched in the most mature CD69 − CD62L + SP4 thymocyte subset. Further examination showed these structures to be enlarged PVS that were surrounding thymic blood vessels.…”

Section: The Type 2 Il‐4r and Thymic Emigrationmentioning

confidence: 92%

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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A type 2 cytokine axis for thymus emigration

Abstract: White et al. describe a new mechanism of thymus emigration that is controlled by expression of the type 2 IL-4 receptor by thymic stroma and production of IL-4 and IL-13 by thymic-resident invariant NKT cells.

Cited by 37 publications

References 53 publications

Rethinking Thymic Tolerance: Lessons from Mice

Rethinking Thymic Tolerance: Lessons from Mice

Recombinant interleukin‐4 alleviates mechanical allodynia via injury‐induced interleukin‐4 receptor alpha in spinal microglia in a rat model of neuropathic pain

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

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