Phenotype, Localization, and Mechanism of Suppression of CD4<b>+</b>CD25<b>+</b> Human Thymocytes

Annunziato, Francesco; Cosmi, Lorenzo; Liotta, Francesco; Lazzeri, Elena; Manetti, Roberto; Vanini, Vittorio; Romagnani, Paola; Maggi, Enrico; Romagnani, Sergio

doi:10.1084/jem.20020110

Cited by 360 publications

(338 citation statements)

References 23 publications

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“…T reg cells suppress activity and proliferation of both CD4 ϩ CD25 Ϫ and CD8 ϩ T cells 12 in a contact-dependent manner through inhibition of interleukin 2 production, 13 express high level intracellular CTLA-4, and do not proliferate in vitro following T-cell receptor stimulation. 14 Recent murine studies indicate that Foxp3 is a specific marker of T reg cells, 15,16 and although human studies suggest that Foxp3 induction can be induced in other CD4 ϩ cells, these studies confirm that Foxp3 induction is associated with suppressive activity. 17 T reg cells secrete transforming growth factor (TGF)-␤1 and interleukin 10 18,19 and may express membrane-bound TGF-␤1, the levels of which are increased upon stimulation in vitro.…”

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confidence: 63%

Compromised lymphocytes infiltrate hepatocellular carcinoma: The role of T-regulatory cells

et al. 2005

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H epatocellular carcinoma (HCC), the fifth most common cancer worldwide with 564,000 new cases each year, is also the third most common cause of cancer-related death. 1 HCC arises most frequently in males with cirrhosis, which is most often a consequence of chronic hepatitis infection or alcohol abuse. 2 Recent reports from different countries suggest that the incidence of HCC is increasing, probably as a consequence of the increased prevalence of hepatitis C virus (HCV) infection, although increased alcohol consumption may be significant. 3 The only effective approaches for patients with HCC are resection or liver transplantation. Following transplantation, there is an 83% 4-year recurrence-free survival in highly selected patients (single tumor Ͻ5 cm in diameter or fewer than three tumors Ͻ3 cm in diameter). 4 However, the majority of patients do not meet such strict criteria or have other contraindications. Local therapies such as percutaneous ethanol injection, thermal ablation, and intra-arterial chemoembolization are less successful, 5 and less than 10% of patients with moderate disease (Okuda stage 2) survive for 3 years. 6 Immunological mechanisms are important in the surveillance of malignancy and control of tumor progression. Cytotoxic CD8 ϩ lymphocytes (CTLs) and natural killer cells are potential effector cells in the control of tumor growth, although both require CD4 ϩ T helper 1 immune responses for optimal function. 7 Tumor-infiltrating lym-

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confidence: 63%

Compromised lymphocytes infiltrate hepatocellular carcinoma: The role of T-regulatory cells

et al. 2005

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“…The CCR9 ligand CCL25 is expressed by thymic epithelial cells and dendritic cells (50,51), and provides the signal important for their localization in the subcapsular region of the thymus (44,52). The major CCR8 ligand CCL1 is expressed by thymic macrophages and fibrous septa epithelial cells (53). A CCR7 ligand CCL19 is predominantly expressed in the medulla including endothelial venules (54).…”

Section: Discussionmentioning

confidence: 99%

FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues

Lee

Kang

Kim

2007

The Journal of Immunology

112

128

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Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3+ T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3+ T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4+ T cells as well as unique to the FoxP3+ cell lineage. In the thymus, precursors of FoxP3+ cells undergo the first trafficking receptor switch (CCR8/CCR9→CXCR4→CCR7), generating mostly homogeneous CD62L+CCR7+CXCR4lowFoxP3+ T cells. CXCR4 expression is regained in FoxP3+ thymic emigrants in the periphery. Consistent with this switch, recent FoxP3+ thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3+ thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3+ T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3+ and FoxP3− T cell populations is that FoxP3+ T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3− T cells, generating FoxP3+ T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues.

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“…Suppressive function was ascribed to CD25 1 CD4SP thymocytes, but also to the CD25 1 DP and CD25 1 CD8SP populations [11,12,14,[16][17][18]. We and others have assessed FOXP3 expression in the human thymus and reported its expression at early stages of T-cell development, likely impacting on the diversity and autoreactivity of the Tregcell repertoire [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…Tregcell lineage commitment is thought to occur within a very narrow window of affinity of TCR-ligand interactions between positive selection of conventional T cells and negative selection of highaffinity self-reactive T cells [8,9]. Indeed, increased self-reactivity is considered a hallmark of Treg cells [10].Initial studies in human fetal and pediatric thymuses, relying on IL-2 receptor a chain (IL-2Ra, CD25) as a Treg-cell marker, identified CD25 expression in CD4SP, as well as in DP and CD8SP, thymocytes [11][12][13][14][15][16][17]. Suppressive function was ascribed to CD25 1 CD4SP thymocytes, but also to the CD25 1 DP and CD25 1 CD8SP populations [11,12,14,[16][17][18].…”

mentioning

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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Phenotype, Localization, and Mechanism of Suppression of CD4+CD25+ Human Thymocytes

Cited by 360 publications

References 23 publications

Compromised lymphocytes infiltrate hepatocellular carcinoma: The role of T-regulatory cells

Compromised lymphocytes infiltrate hepatocellular carcinoma: The role of T-regulatory cells

FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues

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

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