Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition

Weist, Brian M.; Kurd, Nadia; Boussier, Jérémy; Chan, Shiao Wei; Robey, Ellen

doi:10.1038/ni.3171

Cited by 91 publications

(97 citation statements)

References 49 publications

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“…CD8 low Sirpalpha þ cDCs in the thymus demonstrate a superior capacity to induce Treg cells [32], while in human thymic CD11c þ DCs are activated by Hassall's corpuscles derived thymic stromal lymphopoietin (TSLP) to induce the differentiation of Treg cell [33]. A recent study further showed that IL-2 produced by antigen-bearing thymic DCs had a key role in Treg cell development [34]. Meanwhile, CD8a þ cDCs induce negative selection of auto-reactive CD4 þ and CD8 þ T cells via capturing tissue-specific antigens from medullary thymic epithelial cells [35].…”

Section: Subsetsmentioning

confidence: 95%

Regulatory dendritic cells in autoimmunity: A comprehensive review

Liu

Cao

2015

Journal of Autoimmunity

104

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Section: Subsetsmentioning

confidence: 95%

Regulatory dendritic cells in autoimmunity: A comprehensive review

Liu

Cao

2015

Journal of Autoimmunity

104

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“…31,35 In healthy adults, limited availability of IL-2 in the thymic microenvironment favors production of CD4Tcons. 36,37 Early after transplant, CD4Tcon RTEs are maintained within the high normal range but very few CD4Treg RTEs are produced for at least 2 years. CD8 RTEs do not express a unique phenotype, but the frequency of naive CD8 T cells is relatively normal after transplant.…”

Section: Discussionmentioning

confidence: 99%

Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

Alho

Kim

Chammas

et al. 2016

Blood

142

137

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• Homeostatic recovery after allogeneic HSCT favors the production, expansion, and survival of effector T cells over CD4Tregs.• Unbalanced reconstitution of regulatory and effector T-cell subsets contributes to the development of chronic graftversus-host disease.The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. (Blood. 2016;127(5):646-657)

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“…Although this population is enriched for thymocytes with the potential to develop into CD25+FoxP3+ Tregs, further commitment to the Treg lineage requires IL-2 induced signaling though the signal transducer STAT5, which results in the expression of FoxP3 (45, 46). Although these two events can occur sequentially, we have recently demonstrated that the spatiotemporal linkage of these two signals results in greatly enhanced Treg development in situ (15). We also provided evidence that DCs within the thymus are a potent source of IL-2 for Treg development (15).…”

Section: Spatial and Temporal Aspects Of Agonist Selection In The Thymusmentioning

confidence: 99%

T‐cell selection in the thymus: a spatial and temporal perspective

Kurd

Robey

2016

Immunological Reviews

Self Cite

104

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Summary The ability of T cells to respond to a wide array of foreign antigens while avoiding reactivity to self is largely determined by cellular selection of developing T cells in the thymus. While a great deal is known about the cell types and molecules involved in T cell selection in the thymus, our understanding of the spatial and temporal aspects of this process remain relatively poorly understood. Thymocytes are highly motile within the thymus and travel between specialized microenvironments at different phases of their development while interacting with distinct sets of self-peptides and peptide presenting cells. A knowledge of when, where, and how thymocytes encounter self-peptide MHC ligands at different stages of thymic development is key to understanding T cell selection. In the past several years, our laboratory has investigated this topic using two-photon time-lapse microscopy to directly visualize thymocyte migration and signaling events, together with a living thymic slice preparation to provide a synchronized experimental model of T cell selection in situ. Here, we discuss recent advances in our understanding of the temporal and spatial aspects of T cell selection, highlighting our own work, and placing them in the context of work from other groups.

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Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition

Cited by 91 publications

References 49 publications

Regulatory dendritic cells in autoimmunity: A comprehensive review

Regulatory dendritic cells in autoimmunity: A comprehensive review

Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

T‐cell selection in the thymus: a spatial and temporal perspective

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