Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death

Fritzsching, Benedikt; Oberle, Nina; Pauly, Eva; Geffers, Robert; Buer, Jan; Pöschl, Johannes; Krammer, Peter H.; Linderkamp, Otwin; Suri‐Payer, Elisabeth

doi:10.1182/blood-2006-02-005660

Cited by 151 publications

(131 citation statements)

References 37 publications

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“…22 Interestingly, naïve T regs have been shown to possess different functional properties than memory ones, such as resistance toward CD95L-mediated apoptosis. 42 Another possibility for the differential T reg activity in early and late MDS is the variations in TNF-a levels according to the stage of the disease. It has been shown that TNF-a is overexpressed in the early stages of MDS, but is downregulated during disease progression.…”

Section: Discussionmentioning

confidence: 99%

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

et al. 2008

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CD4 þ CD25 þ FOXP3 þ T regulatory cells (T regs ) prevent autoimmunity by restricting overexuberant immune responses, but the same subpopulation can incur detrimental effects on antitumor responses. In both cases, the suppressor potential of T regs appears to be strongly influenced by their compartmentalization. In myelodysplastic syndromes (MDS), immune deregulation and autoimmunity in the early stages might lead to ineffective hematopoiesis and bone marrow (BM) failure, whereas late-stage disease is characterized by the immune escape of the malignant clone. We show that these two stages of MDS are associated with differential T reg activity. Specifically, we found that in early stage MDS, compared with normal hematopoiesis and late stage MDS, T regs are dysfunctional and their BM homing through the CXCL12/CXCR4 axis is seriously impaired as a result of CXCR4 downregulation. Conversely, in late stage MDS, T regs are systemically and locally expanded and retain their function and migratory capacity. Moreover, T reg levels follow the disease course and are significantly reduced in treatment responding patients. Our findings indicate T reg involvement in the pathophysiology of MDS; defective suppressor function and BM trafficking of T regs may be important in the autoimmune process of early MDS, but increased T reg activity could favor leukemic clone progression in late stage disease.

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Section: Discussionmentioning

confidence: 99%

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

et al. 2008

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“…2010. 40: 47- [39,41], but are susceptible to apoptosis following IL-2 deprivation [39]. Produced by activated T cells, IL-2 is necessary to promote Treg expansion [79].…”

Section: Foxp3mentioning

confidence: 99%

“…1 Treg are memory-like T cells, and express high levels of CD95, making them prone to apoptosis [40]; nevertheless a proportion of Treg express a phenotype typical of naïve T cells and -again, as for conventional T cells -these ''naïve'' Treg are apoptosis resistant [41]. Conversely, unlike conventional T cells, freshly isolated Treg are highly prone to CD95L-induced cell death but become resistant to activationinduced cell death when activated [40].…”

Section: Foxp3mentioning

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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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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“…The other population resembles memory cells because of their CD45RA low , CD45RO high , CD95 high phenotype. Most of these memory-like Treg cells express very high levels of CD25 and they are sensitive to CD95-mediated apoptosis [15]. Thus, on the basis of CD25 expression, naïve-like Treg cannot be separated from Teff cells.…”

Section: Foxp3 Represents a Single Definitive Treg Markermentioning

confidence: 99%

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

2006

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Regulatory T cells (Treg) provide protection from autoimmune disease, graft‐versus‐host disease, transplant rejection and overwhelming tissue destruction during infections. Conversely, high Treg numbers enable cancer cells to evade the host immune response. Thus, Treg are seen as an important tool to manipulate the immune response. However, as the immunological community is trying to move this knowledge from mice to humans, contradictory results regarding the number and function of Treg in various diseases are appearing. This problem arises because we cannot clearly define Treg populations on the basis of expression of CD25 and other cell surface markers in humans. This review addresses the utility of the FOXP3 forkhead transcription factor for the identification of Treg populations and summarizes recent data on the expression of FOXP3 in lymphomas. It is crucial to really understand Treg biology before attempting therapies, including (i) the injection of expanded Treg to cure autoimmune disease or prevent graft‐versus‐host disease or (ii) the depletion or inhibition of Treg in cancer therapy. For instance, new data arising from the study of haematological malignancies highlight the additional complexity of systems where malignant cell populations may also be direct Treg targets.

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Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death

Cited by 151 publications

References 37 publications

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

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

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

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Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death

Cited by 151 publications

References 37 publications

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS)

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

FOXP3+ regulatory T cells: Current controversies and future perspectives

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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

FOXP3⁺ regulatory T cells: Current controversies and future perspectives