Thymic emigration revisited

McCaughtry, Tom M.; Wilken, Matthew S.; Hogquist, Kristin A.

doi:10.1084/jem.20070601

Cited by 240 publications

(304 citation statements)

References 37 publications

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“…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. The numerical difference in those populations may be explained by a significant commitment to the Treg-cell lineage at the DP stage together with an accumulation of FOXP3 1 SP cells prior to their exit, due to the time-lag incurred by maturation of cells in the thymic medulla [43]. Recent murine studies have also demonstrated the possibility of Treg-cell generation in the cortex, followed by rapid migration into the medulla, where they mature [44,45].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2011

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“…In this study, we confirmed these results by demonstrating H2BeGFP loss during thymic exit solely for CD8 + and not for CD4 + RTEs. It was speculated that CD8 + thymocytes in RAG2p-GFP transgenic mice showed lower GFP levels because their DP to SP transition took longer time than in CD4 + thymocytes (19). In this study, we observed that decline of H2BeGFP reporter intensity was greater in CD8 + compared with CD4 + T cells.…”

Section: Discussionmentioning

confidence: 47%

“…Earlier studies using these methods suggested intrathymic expansion of mature thymocytes before export to the periphery (17). More recently, BAC-transgenic mice with multiple copies of GFP under the control of the Rag2 promoter (18) were used as a genetic tool to monitor the dynamics of thymic maturation, emigration (19), and to directly identify recent thymic emigrants (RTEs) (20,21). In this Rag2p-GFP system, GFP-reporter transcription terminates after Tcra rearrangement in DP cells, but GFP fluorescence is detectable in peripheral T cells because of the considerable halflife of GFP in mouse T cells estimated to range between 16 and 18 h (20) and 54 and 56 h (19).…”

Section: P Roliferation Of Ab T Cells Occurs At Different Stages Dur-mentioning

confidence: 99%

“…More recently, BAC-transgenic mice with multiple copies of GFP under the control of the Rag2 promoter (18) were used as a genetic tool to monitor the dynamics of thymic maturation, emigration (19), and to directly identify recent thymic emigrants (RTEs) (20,21). In this Rag2p-GFP system, GFP-reporter transcription terminates after Tcra rearrangement in DP cells, but GFP fluorescence is detectable in peripheral T cells because of the considerable halflife of GFP in mouse T cells estimated to range between 16 and 18 h (20) and 54 and 56 h (19). Thus, the observation that the GFP signal in Rag2p-GFP mice lingers in SP thymocytes and RTEs further supports the idea that conventional ab T cells do not cycle much after positive selection.…”

Section: P Roliferation Of Ab T Cells Occurs At Different Stages Dur-mentioning

confidence: 99%

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Differential Postselection Proliferation Dynamics of αβ T Cells, Foxp3+ Regulatory T Cells, and Invariant NKT Cells Monitored by Genetic Pulse Labeling

Föhse

Reinhardt

Oberdörfer

et al. 2013

The Journal of Immunology

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The thymus generates two divergent types of lymphocytes, innate and adaptive T cells. Innate T cells such as invariant NKT cells provide immediate immune defense, whereas adaptive T cells require a phase of expansion and functional differentiation outside the thymus. Naive adaptive T lymphocytes should not proliferate much after positive selection in the thymus to ensure a highly diverse TCR repertoire. In contrast, oligoclonal innate lymphocyte populations are efficiently expanded through intrathymic proliferation. For CD4+Foxp3+ regulatory T cells (Tregs), which are thought to be generated by agonist recognition, it is not clear whether they proliferate upon thymic selection. In this study, we investigated thymic and peripheral T cell proliferation by genetic pulse labeling. To this end, we used a mouse model in which all developing αβ thymocytes were marked by expression of a histone 2B–enhanced GFP (H2BeGFP) fusion-protein located within the Tcrd locus (TcrdH2BeGFP). This reporter gene was excised during TCR α-chain VJ-recombination, and the retained H2BeGFP signal was thus diluted upon cell proliferation. We found that innate T cells such as CD1d-restricted invariant NKT cells all underwent a phase of intense intrathymic proliferation, whereas adaptive CD4+ and CD8+ single-positive thymocytes including thymic Tregs cycled, on average, only once after final selection. After thymic exit, retention or loss of very stable H2BeGFP signal indicated the proliferative history of peripheral αβ T cells. There, peripheral Tregs showed lower levels of H2BeGFP compared with CD4+Foxp3− T cells. This further supports the hypothesis that the Treg repertoire is shaped by self-Ag recognition in the steady-state.

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“…Second, the level of TRA expression per cell is always lower in mTEC than in the corresponding tissue [30]. Third, the average residence time of mature thymocytes of 4 to 5 days is shorter than previously assumed [31,32]. Nevertheless, deletion of monoclonal or polyclonal T-cell repertoires specific for ectopically expressed (neo) self-antigens is highly efficient [33,34].…”

Section: Spatial Is Expressed In Mature Medullary Thymic Epithelial Cmentioning

confidence: 96%

Spatial (Tbata) expression in mature medullary thymic epithelial cells

et al. 2010

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The Spatial gene is expressed in highly polarized cell types such as testis germ cells, brain neurons and thymic epithelial cells (TEC). Its expression was documented in testis and brain but poorly characterized in thymus. Here, we characterize for the first time Spatial-expressing TEC throughout ontogeny and adult mouse thymus. Spatial is expressed in thymicfated domain by embryonic day E10.5 and persists in subcapsular, cortical, medullary epithelial cells and in MTS24 1 progenitor TEC. Using mouse strains in which thymocyte development is blocked at various stages, we show that Spatial expression is independent of thymocyte-derived signals during thymus organogenesis. Analyses on purified thymic cell subsets show that Spatial short isoforms are expressed in cortical TEC (cTEC) and mature medullary TEC (mTEC). Spatial long isoforms were detected in the same TEC population. Spatial presents a nuclear distribution specific to mature mTEC expressing UEA1 and Aire. Aire-and RANKL-deficient mice revealed that Spatial expression is drastically reduced in the thymus of these mutants. These findings reveal a critical function of Aire in regulating Spatial expression, which is compatible with promiscuous Spatial gene expression. 530 IntroductionThe vertebrate thymus is responsible for the production of functional nonautoreactive T lymphocytes. In this primary lymphoid organ, T-cell precursors commonly called thymocytes undergo a series of developmental stages through interactions with thymic stromal cells, resulting in the generation of mature T lymphocytes that are exported to the periphery [1,2]. The unique function of the thymus resides mainly in the thymic epithelium, which forms the major subcompartment of the stroma [3,4]. The thymic epithelium itself is commonly divided into two main regions, the cortex and the medulla, and each of these regions contains several ultrastructurally and phenotypically distinct types of thymic epithelial cells (TEC) [5,6]. TEC are required both for thymus organogenesis and for the promotion of most if not all stages of thymocyte maturation [3,4]. Understanding the molecular mechanisms regulating TEC differentiation and function provides crucial insights into mechanisms controlling T-cell development in the thymus.Using DNA chip technology we isolated the Spatial gene (Stromal Protein Associated with Thymii and Lymph node), also known as Tbata (thymus, brain and testes associated), by an approach based on differential screening between different knock-out mice models exhibiting distinct thymic immunodeficiencies [7]. This analysis led to the identification of three adult variants of the Spatial gene expressed in the thymus [8]. In addition, we also described two other isoforms isolated in the testis [8][9][10]. According to the size of alternative spliced variants, we have respectively named Spatial isoforms: Spatial-a (1035 bp), Spatial-b (1002 bp), Spatial-g (933 bp) for the short isoforms identified in the thymus; Spatial-d (1353 bp) and Spatial-e (1454 bp) for the long isoforms ...

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Thymic emigration revisited

Cited by 240 publications

References 37 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

Differential Postselection Proliferation Dynamics of αβ T Cells, Foxp3+ Regulatory T Cells, and Invariant NKT Cells Monitored by Genetic Pulse Labeling

Spatial (Tbata) expression in mature medullary thymic epithelial cells

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