Human regulatory T cells and autoimmunity

Costantino, Cristina Maria; Baecher-Allan, Clare; Hafler, David A.

doi:10.1002/eji.200738104

Cited by 138 publications

(114 citation statements)

References 29 publications

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Section: Introductionmentioning

confidence: 99%

“…With such a broad range of effects and mechanisms of action, it seems plausible that different subsets of natural Treg may exist. Indeed, it is increasingly recognised that human Treg are far more heterogenous than murine Treg [9], and that even CD4 [37]. Functionally distinct Treg subpopulations have also been identified on the basis of forkhead box P3 (FOXP3) expression intensity and CD45RA expression [10].…”

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confidence: 99%

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Phenotypic analysis of human peripheral blood regulatory T cells (CD4⁺FOXP3⁺CD127^lo/–) ex vivo and after in vitro restimulation with malaria antigens

2009

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Regulatory T cells (Treg) play crucial roles in regulating autoimmune responses and immunity to tumors and infectious diseases. However, numerous subpopulations of Treg are now being described and the utility of various Treg markers is being reassessed. Here we report the results of a detailed phenotypic comparison of two supposedly regulatory human T-cell populations, namely CD4 1 FOXP31 T cells and CD4 (CCR), CD95 and Bcl-2, suggestive of distinct migration characteristics and susceptibility to apoptosis. Further, we propose that CD25 expression should be regarded as an activation marker rather than as a defining marker of Treg. Lastly, CD4 1 FOXP3 1 T cells activated in vitro with malaria antigen expressed the highest levels of CCR4 and CD95, and the lowest levels of CCR7, indicating that they are most likely generated from effector memory cells during an immune response and rapidly succumb to apoptosis at the end of the response. [7]. A plethora of different regulatory mechanisms has been identified (reviewed by [8]). With such a broad range of effects and mechanisms of action, it seems plausible that different subsets of natural Treg may exist. Indeed, it is increasingly recognised that human Treg are far more heterogenous than murine Treg [9], and that even CD4 [37]. Functionally distinct Treg subpopulations have also been identified on the basis of forkhead box P3 (FOXP3) expression intensity and CD45RA expression [10].We have previously reported that in areas of seasonal malaria transmission, Treg may expand alongside effector memory (EM) T cells when malaria exposure is high, and that both populations may contract once exposure decreases [38]; this contraction may involve apoptotic pathways. Treg have been shown to be highly susceptible to spontaneous cell death or cytokine-deprivation induced death [39]. As for conventional T cells, it has been shown that the majority of CD4 T cells with regard to the expression of CCR and apoptotic molecules and suggest that CD25, rather than being a marker of Treg per se, is a marker of activated Treg. Given our interest in Treg function during malaria infection [38,[44][45][46][47], we further aimed to study these markers in relation to Treg activation status in vitro, using Plasmodium falciparum schizont extract (PfSE). Importantly, we show that -irrespective of the culture conditions -the phenotype of FOXP3 1 T cells is modified when they are kept in in vitro culture, affecting both expression of CCR and molecules involved in apoptosis, indicating a need for caution when comparing data from in vitro and ex vivo studies. Results CD25 -a Treg-identifying marker or a marker of Treg activation?Whole blood from 28 adult Gambian donors was stained ex vivo and viable lymphocytes were gated for CD4 and CD25 expression.The double negative (CD4 -CD25 -) population was used to define the cut-off for CD4 and CD25 expression (Fig. 1A) (Fig. 2D) and expressing significantly higher levels of CD95 than the CD25 -or CD25 lo populations (Fig. 2E). However, importantly, both the l...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Phenotypic analysis of human peripheral blood regulatory T cells (CD4⁺FOXP3⁺CD127^lo/–) ex vivo and after in vitro restimulation with malaria antigens

2009

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“…Predominantly derived from a distinct T cell subpopulation in the thymus, CD4 + Foxp3 + Treg principally recognize self-antigens and are required to control the expansion of self-reactive T cells in the peripheral lymphoid organs (2,3). In view of that, there is increasing evidence that numeric or functional Treg deficiencies are associated with particular autoimmune diseases, suggesting a contribution of a Treg dysfunction to disease development (4).…”

mentioning

confidence: 99%

Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus

Humrich

Morbach²,

Undeutsch

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

125

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The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F 1 mouse model of lupus, we found that CD4 + Foxp3 + Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting in a progressive homeostatic imbalance of CD4 + Foxp3 + Treg and CD4 + Foxp3 − conventional T cells (Tcon). In addition, Treg acquired phenotypic changes that are reminiscent of IL-2 deficiency concomitantly to a progressive decline in IL-2-producing Tcon and an increase in activated, IFN-γ-producing effector Tcon. Nonetheless, Treg from lupus-prone mice were functionally intact and capable to influence the course of disease. Systemic reduction of IL-2 levels early in disease promoted Tcon hyperactivity, induced the imbalance of Treg and effector Tcon, and strongly accelerated disease progression. In contrast, administration of IL-2 partially restored the balance of Treg and effector Tcon by promoting the homeostatic proliferation of endogenous Treg and impeded the progression of established disease. Thus, an acquired and self-amplifying disruption of the Treg-IL-2 axis contributed essentially to Tcon hyperactivity and the development of murine lupus. The reversibility of this homeostatic Treg disorder provides promising approaches for the treatment of SLE.

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“…The expression of regulatory T cell (Treg) specific transcription factors such as Foxp3 (Costantino et al, 2008;Wang et al, 2013) was not assessed in this study. However, the rather low percentage of CD4+CD25+ T cells [(0.73±1.33)%] implied that the proportion of Treg cells was extremely low in EAAL cells.…”

Section: Discussionmentioning

confidence: 99%

Adoptive Immunotherapy for Small Cell Lung Cancer by Expanded Activated Autologous Lymphocytes: a Retrospective Clinical Analysis

Zhang

Li²,

Sun³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: To investigate the clinical efficacy of expanded activated autologous lymphocytes (EAAL) in patients with small cell lung cancer (SCLC). Materials and Methods: A total of 32 SCLC patients were selected and randomly divided into EAAL treatment and control groups, 16 cases in each. EAAL were obtained by proliferation of peripheral blood mononuclear cells (PBMCs) of patients followed by phenotype determination. Clinical data of all patients were recorded. Patients of both groups were followed up and the overall survival (OS) were compared retrospectively. Results: After culture and proliferation in vitro, the percentages of CD3 + , CD3 + CD8 + , CD45RO + , CD28 + , CD29 + , CD8 + CD28 + and CD3+CD16+/CD56+ cells increased markedly (p<0.05). The OS of the EAAL treatment group was longer than that of control group, but the difference was not statistically significant (p=0.060, HR=0.487, 95%CI 0.228~1.037). 1-to 3-year survival rates in EAAL treatment group were longer than those in control group, but there was still no significant difference (p>0.05). COX multivariate regression analysis showed that the number of chemotherapy cycles and the application of EAAL immunotherapy were independent prognostic factors for SCLC patients. The OS in females and chemotherapy≤6 cycles were obviously prolonged after EAAL immunotherapy. Conclusions: In vitro induction and proliferation of EAAL is easy and biologically safe. Generally, EAAL adoptive immunotherapy can evidently prolong the OS of SCLC patients.

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Human regulatory T cells and autoimmunity

Cited by 138 publications

References 29 publications

Phenotypic analysis of human peripheral blood regulatory T cells (CD4⁺FOXP3⁺CD127^lo/–) ex vivo and after in vitro restimulation with malaria antigens

Phenotypic analysis of human peripheral blood regulatory T cells (CD4⁺FOXP3⁺CD127^lo/–) ex vivo and after in vitro restimulation with malaria antigens

Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus

Adoptive Immunotherapy for Small Cell Lung Cancer by Expanded Activated Autologous Lymphocytes: a Retrospective Clinical Analysis

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Human regulatory T cells and autoimmunity

Cited by 138 publications

References 29 publications

Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/–) ex vivo and after in vitro restimulation with malaria antigens

Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/–) ex vivo and after in vitro restimulation with malaria antigens

Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus

Adoptive Immunotherapy for Small Cell Lung Cancer by Expanded Activated Autologous Lymphocytes: a Retrospective Clinical Analysis

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Phenotypic analysis of human peripheral blood regulatory T cells (CD4⁺FOXP3⁺CD127^lo/–) ex vivo and after in vitro restimulation with malaria antigens

Phenotypic analysis of human peripheral blood regulatory T cells (CD4⁺FOXP3⁺CD127^lo/–) ex vivo and after in vitro restimulation with malaria antigens