Different Proliferative Potential and Migratory Characteristics of Human CD4+ Regulatory T Cells That Express either CD45RA or CD45RO

Booth, Nicola J.; McQuaid, A; Sobande, T; Kissane, Steve; Agius, Elaine; Jackson, Sarah E.; Salmon, Mike; Falciani, Francesco; Yong, Kwee; Rustin, M.H.A.; Akbar, Arne N.; Vukmanovic‐Stejic, Milica

doi:10.4049/jimmunol.0903781

Cited by 202 publications

(196 citation statements)

References 50 publications

(87 reference statements)

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“…Accordingly, a recent study reported the lack of CD73 expression by circulating human CD4 1 Treg cells [38]. Furthermore, our results allocate the acquisition of CD73 to CD8SP cells in the thymus, which, on egress, will most likely enrich the pool of CD73 1 naïve CD8 1 T cells described in humans [39].…”

supporting

confidence: 53%

“…In agreement, the expression of CD45RA in CD4SP human thymocytes [37] and in FOXP3 1 CD4 1 T cells [28] was associated with low levels of CD25. In addition, the fraction of FOXP3 1 CD45RA 1 CD4 1 T cells expressing CD39 in the periphery was shown to be negligible [38].Conversely, we showed that the expression of CD73, an ectoenzyme that, in conjunction with CD39, generates the suppressive molecule adenosine, was mainly restricted to CD8SP cells, and this was observed irrespectively of FOXP3 expression. Accordingly, a recent study reported the lack of CD73 expression by circulating human CD4 1 Treg cells [38].…”

mentioning

confidence: 57%

Section: Discussionmentioning

confidence: 97%

“…In addition, the fraction of FOXP3 1 CD45RA 1 CD4 1 T cells expressing CD39 in the periphery was shown to be negligible [38].…”

mentioning

confidence: 97%

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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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supporting

confidence: 53%

mentioning

confidence: 57%

Section: Discussionmentioning

confidence: 97%

“…In addition, the fraction of FOXP3 1 CD45RA 1 CD4 1 T cells expressing CD39 in the periphery was shown to be negligible [38].…”

mentioning

confidence: 97%

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

et al. 2011

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“…Survival analysis and correlation of pretreatment percentages of the two Treg subsets with overall survival rate, showed that patients with higher percentages of nTregs had a better survival. nTregs differentiate into aTregs upon T-cell receptor stimulation by antigen recognition, 24,44,45 which could imply that patients having a relatively high percentage of peripheral nTregs have less tumor-specific Tregs. Due to their naïve phenotype, these nTregs are inefficient in infiltrating the tumor, 46 as is also illustrated by their low CCR4 expression, and thus these cells cannot exert immunosuppressive activity.…”

Section: Discussionmentioning

confidence: 99%

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

et al. 2018

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Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs.Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients.Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry.Results: After one week treatment with mCTX, both activated FoxP3hi and naïve CD45RA+ Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased.Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment.

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Increased T Cell Plasticity With Dysregulation of Follicular Helper T, Peripheral Helper T, and Treg Cell Responses in Children With Juvenile Idiopathic Arthritis and Down Syndrome–Associated Arthritis

Foley

Floudas

Canavan

et al. 2020

Arthritis & Rheumatology

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Objective Juvenile idiopathic arthritis (JIA) is the most common inflammatory arthritis in children; however, an aggressive, erosive arthritis of little‐known immunologic mechanism occurs 20 times more frequently in children with Down syndrome. This study was undertaken to characterize T cell and B cell polyreactivity, follicular helper T (Tfh) cell, peripheral helper T (Tph) cell, and Treg cell responses, and synovial inflammation in Down syndrome–associated arthritis (DA). Methods Multiparametric flow cytometric analysis and Simplified Presentation of Incredibly Complex Evaluations (SPICE) software were used to examine peripheral blood B cell populations and T cell cytokine responses in patients with DA, JIA, Down syndrome (trisomy 21 [T21]), and in healthy controls. Tfh and Tph cell frequency and origin, in addition to Treg cell frequency, were also evaluated. Synovial inflammation was assessed by immunohistology. Results Expansion of IgM‐only memory B cells was demonstrated in DA compared to JIA (mean ± SEM 22.48 ± 3.278 versus 9.011 ± 1.317; P = 0.005), paralleled by decreased frequency of transitional B cells. T cell responses in DA were characterized by marked functional plasticity, as was evident from the increased frequency of polyfunctional CD8+ Th cells (P < 0.05), CD161+ Th cells (P < 0.05), and CD8− Th cells (P < 0.001), and positivity for tumor necrosis factor, interferon‐γ, interleukin‐17A, or granulocyte–macrophage colony‐stimulating factor, compared to all other groups. Significant expansion of CXCR3+CCR6+ (Th1/Th17) Tfh cells (P = 0.003) and CXCR3+CCR6+ Tph cells (P = 0.01), paralleled by a decrease in CXCR3−CCR6− (Th2) Tfh cells was observed in DA compared to T21. Treg cells were significantly reduced in DA compared to T21 (mean ± SEM 7.111 ± 0.9518 versus 11.96 ± 1.055 versus; P = 0.0028), with a specific reduction in the naive:memory Treg cell ratio. Marked synovial tissue inflammation and increased T cell and B cell infiltrations were demonstrated in DA compared to JIA. Conclusion DA is more common and more aggressive than JIA. It is characterized by increased polyreactive Th, Tfh, and Tph cell responses, reduced Treg cell frequency, and evidence of increased synovial inflammation, all of which are potentially distinct from JIA and T21.

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Different Proliferative Potential and Migratory Characteristics of Human CD4+ Regulatory T Cells That Express either CD45RA or CD45RO

Abstract: Material

Cited by 202 publications

References 50 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

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

Increased T Cell Plasticity With Dysregulation of Follicular Helper T, Peripheral Helper T, and Treg Cell Responses in Children With Juvenile Idiopathic Arthritis and Down Syndrome–Associated Arthritis

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