Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus

Watanabe, Norihiko; Wang, Yi Hong; Lee, Kyung-Mi; Ito, Tomoki; Wang, Yui Hsi; Cao, Wei; Liu, Yong Jun

doi:10.1038/nature03886

Cited by 669 publications

(584 citation statements)

References 26 publications

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“…In agreement, it was recently suggested that human Treg-cell progenitors may selectively reside within mature DP thymocytes expressing high levels of CD69 and TCR-ab, since these cells develop into CD4SP Treg cells in response to activated autologous plasmacytoid and myeloid DCs [40], although not excluding the possibility of FOXP3 induction at the SP stages [41,42]. Additionally, our multiple regression analyses show a significant statistical dependency of the FOXP3 1 DP and SP populations, further supporting their direct precursor-product association.…”

Section: Discussionmentioning

confidence: 74%

Differentiation of human thymic regulatory T cells at the double positive stage

et al. 2011

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Treg cells, best identified by the expression of the transcription factor FOXP3, play a crucial role in maintaining self-tolerance. Natural Treg cells constitute an independent thymusderived T-cell lineage whose developmental program in humans is still ill-defined. Here, we provide evidence of a Treg-cell differentiation pathway at the double positive (DP) stage, prior to commitment to the CD4 1 or CD8 1 lineage, in pediatric thymuses. FOXP3 1 DP cells displayed a functional IL-7 receptor and increased Bcl-2 levels that may protect them from cell death/negative selection, and an activated/suppressive phenotype that was lost as CD4 single positive (SP) cells matured and acquired egress markers. A subpopulation of FOXP3 1 DP thymocytes expressing CD103 likely represents the precursor of FOXP3 1 CD8SP cells, which homogeneously expressed this mucosal-homing molecule. Finally, co-cultures of DP thymocytes with primary thymic epithelial cells and multiple linear regression analyses support that FOXP3 1 SP cells are largely derived from FOXP3 1 DP thymocytes. Overall, our data suggest that human Treg-cell lineage commitment significantly occurs at the DP stage with possible implications for the diversity and autoreactivity of the natural Treg-cell repertoire.Key words: FOXP3 . Human T-cell development . Treg cells . Thymus Supporting Information available online IntroductionThe thymus is essential for the establishment and renewal of the peripheral T-cell compartment with a diverse repertoire, able to efficiently respond to novel pathogens, yet tolerant to selfantigens. Tolerance is at least partly achieved through the thymic production of a subset of T cells termed ''natural'' Treg cells. Treg cells modulate the activation and function of other T cells, as well as of other cell populations of the immune system, playing important roles not only in the prevention of autoimmune diseases, but also in other clinical settings, such as tumor immunity and persistent infections [1,2]. Currently, the forkhead/winged-helix transcription factor FOXP3 is considered as the best available marker to identify Treg cells. The essential role of FOXP3 in human Treg-cell development and function is attested by the association of FOXP3 defects with the fatal condition IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome [3]. Although understanding Treg-cell development in the human thymus is critical for their manipulation [4], the developmental program that Treg-cell precursors undergo to give rise to mature FOXP3 1 cells is still unclear. 3604T-cell development proceeds through a series of stages that can be tracked by the expression of CD3, CD4 and CD8. In humans, CD4 -CD8 -CD3 -triple negative cells first acquire CD4 (CD4 1 immature single positive) and then CD8 to become CD4 1 CD8 1 (double positive, DP) cells. DP cells bearing TCR-ab complexes able to engage self-MHC molecules are signaled to survive (positive selection) and to differentiate into functionally mature CD4 1 single positive (CD4SP; CD4 1 CD8...

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Section: Discussionmentioning

confidence: 74%

Differentiation of human thymic regulatory T cells at the double positive stage

et al. 2011

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“…DC can differentiate T regs in the thymus [78] and in the periphery [79], and expand them once the T regs have formed [80][81][82]. Antigen-specific T regs are much more effective than polyclonal populations in suppressing immunity in vivo [79,[81][82][83].…”

Section: Tolerogenicity Another Side Of Immunogenicitymentioning

confidence: 99%

Dendritic cells: Understanding immunogenicity

2007

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The impetus for the discovery of dendritic cells in 1972 was to understand immunogenicity, the capacity of an antigenic substance to provoke immunity. During experiments to characterize "accessory" cells that enhanced immunity, we spotted unusual stellate cells in mouse spleen. They had a distinct capacity to form and retract processes or dendrites and were named dendritic cells (DC). DC proved to be different from other cell types and to be peculiarly immunogenic when loaded with antigens. When Langerhans cells were studied, immunogenicity was found to involve two steps: antigen presentation by immature DC and maturation to elicit immunity. Antigenbearing DC were also immunogenic in vivo and were therefore termed "nature's adjuvants". Several labs then learned to generate large numbers of DC from progenitors, which accelerated DC research. Tolerogenicity via DC, including the control of foxp3 + suppressor T cells, was recently discovered. Two areas of current research that I find intriguing are to identify mechanisms for antigen uptake and processing, and for the control of different types of immunity and tolerance. These subjects should be studied in vivo with clinically relevant antigens, so that the activities of DC can be better integrated into the prevention and treatment of disease in patients.

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“…The expression of AIRE in the thymic MECs is believed to play a role in the negative selection of autoreactive T cells (4 -7), but another structure, the epithelial Hassall's corpuscle, seems to be important in the positive selection of human CD25 ϩ Treg cells (31). We therefore examined the relationship of AIRE ϩ cells and Hassall's corpuscles in four different thymic tissues.…”

Section: Expression Of Aire In Human Thymusmentioning

confidence: 99%

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Kekäläinen¹,

Tuovinen²,

Joensuu³

et al. 2007

The Journal of Immunology

189

142

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire−/− mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire−/− mice, in the patients a key mediator of active tolerance, the CD4+CD25+ regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE+ cells was seen around thymic Hassall’s corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire−/− mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.

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Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus

Cited by 669 publications

References 26 publications

Differentiation of human thymic regulatory T cells at the double positive stage

Differentiation of human thymic regulatory T cells at the double positive stage

Dendritic cells: Understanding immunogenicity

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

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