A peripheral circulating compartment of natural naive CD4+ Tregs

Valmori, Danila; Merlo, Andrea; Souleimanian, Naira E.; Hesdorffer, Charles; Ayyoub, Maha

doi:10.1172/jci23963

Cited by 268 publications

(289 citation statements)

References 45 publications

(40 reference statements)

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“…Contrary to earlier reports, human CD4 1 CD25 high Treg in adult peripheral blood have recently been shown to comprise not only (self-)antigen-experienced, CD45RA À central and effector memory cells, but also a subpopulation of CD45RA 1 naïve recent thymic emigrants [14,15]. We previously demonstrated that these CD45RA 1 CD4 1 CD25 high T cells (RA 1 Treg) homogeneously maintain their Treg cell phenotype and function upon in vitro expansion, whereas CD4 1 T cells selected solely for CD25 high expression were highly variable with respect to FOXP3 expression (50.5 to 72.8% FOXP3 1 cells) after long-term culture [16].…”

Section: Introductionmentioning

confidence: 78%

“…Together with the heterogeneity of long-term cultured Treg cell clones derived from CD45RA 1 naïve Treg, these findings definitely prove that FOXP3 expression can be lost in natural Treg and suggest that FOXP3 down-regulation (at least partially) depends on the number of re-stimulation cycles. While antigen-experienced CD45RA À Treg most likely went through TCR-stimulation episodes already in vivo before isolation, CD45RA 1 Treg mostly represent recent thymic emigrants without previous exposure to extrathymic self or foreign antigens [14,15]. Although Treg that lose FOXP3 expression upon expansion gain the ability to secrete proinflammatory cytokines (IL-2, IFN-g), they do not seem to convert completely to Tconv, as they also secrete large amounts of IL-10.…”

Section: Discussionmentioning

confidence: 99%

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Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

et al. 2009

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The adoptive transfer of CD4 1 CD25 1 natural regulatory T cells (Treg) is a promising strategy for the treatment of autoimmune diseases and the prevention of alloresponses after transplantation. Clinical trials exploring this strategy require efficient in vitro expansion of this rare cell population. Protocols developed thus far rely on high-grade purification of Treg prior to culture initiation, a process still hampered by the lack of Treg cell-specific surface markers. Depletion of CD127 1 cells was shown to separate activated conventional T cells from natural Treg cell populations allowing the isolation of highly enriched FOXP3 1 cells with all functional and molecular characteristics of natural Treg. Here, we demonstrate that upon in vitro expansion, CpG methylation in a conserved region within the FOXP3 gene locus increased in CD4 1 CD25 1 CD127 low Treg, correlating with loss of FOXP3 expression and emergence of pro-inflammatory cytokines. Further analysis identified CD45RA À FOXP3 1 memory-type Treg as the main source of converting cells, whereas CD45RA 1 FOXP3 1 Treg from the same donors showed no conversion within 3 wk of in vitro expansion. Thus, Treg cell lineage differentiation does not seem to represent a final fate decision, as natural Treg can lose their cell-type-specific characteristics after repetitive TCR stimulation.Key words: Cellular therapy . Immune regulation . Treg Supporting Information available online Introduction CD4 1 CD25 1 Treg are pivotal for the maintenance of peripheral self-tolerance and imbalances in this T-cell compartment have been shown to contribute to various autoimmune diseases [1]. In murine disease models, adoptively transferred Treg prevent, and in some cases, even cure autoimmunity [2,3]. In addition, they protect from graft rejection after allogeneic organ transplantation [4] as well as from graft-versus-host disease after MHCmismatched stem cell transplantation [5][6][7][8]. Recently, a limited number of Phase I clinical trials exploring the adoptive transfer of Treg have been initiated and several additional trials in various clinical settings are in preparation [9,10]. Prerequisites for the initiation of such trials are (i) the availability of efficient in vitro expansion protocols for this rare cell population and (ii) the ability to unequivocally identify Treg to avoid contamination of 1088Treg cultures with potentially harmful conventional effector T cells (Tconv). While efficient cell culture protocols have recently been established by us and others for the polyclonal as well as antigen-specific Treg cell expansion [11][12][13], the search for an exclusive surface marker for Treg is still ongoing.Contrary to earlier reports, human CD4 1 CD25 high Treg in adult peripheral blood have recently been shown to comprise not only (self-)antigen-experienced, CD45RA À central and effector memory cells, but also a subpopulation of CD45RA 1 naïve recent thymic emigrants [14,15]. We previously demonstrated that these CD45RA 1 CD4 1 CD25 high T cells (RA 1 Treg) homogen...

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Section: Introductionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

et al. 2009

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“…First, the lack of a specific marker for Treg has led to the assumption that only CD4ϩ,CD25 high T cells represent human Treg. (25,(38)(39)(40). However, it is unclear whether the reported reduction in the number of CD4ϩ,CD25 high Treg in SLE is compensated by an increase in the number of CD25 low ,Foxp3ϩ Treg that was not analyzed in previous studies.…”

Section: Discussionmentioning

confidence: 96%

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Franz¹,

Fritzsching²,

Riehl³

et al. 2007

Arthritis & Rheumatism

123

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Objective. To define the phenotype and function of CD4؉,CD25؉ regulatory T cells (Treg) in patients with cutaneous lupus erythematosus (CLE), a heterogeneous autoimmune disease characterized primarily by inflammatory skin lesions.Methods. The number of Treg in skin specimens obtained from patients with various subtypes of CLE was investigated by immunohistochemical analysis, using anti-Foxp3 and anti-CD4 monoclonal antibodies. Furthermore, characterization of peripheral blood CD4؉,CD25؉ Treg from normal healthy donors and patients with CLE was carried out by flow cytometry, analyzing the expression of Foxp3 and Treg subpopulations. We also purified CD4؉,CD25 high Treg obtained from patients with CLE and tested the sensitivity of these cells to CD95L-mediated apoptosis.Results. Quantitative analysis of CD4؉ T cells in skin lesions from patients with CLE revealed that the number was similar to that in lesions from patients with other chronic inflammatory diseases, but the number of Foxp3؉ Treg in CLE was significantly reduced. There was no correlation between disease subtype and the frequency of Foxp3؉ Treg in the skin of patients with CLE. In peripheral blood, no significant differences were observed in the number and phenotype of CD4؉,CD25؉ Treg or in the sensitivity to apoptosis of CD4؉,CD25 high Treg derived from patients with CLE and those derived from normal healthy donors.Conclusion. These data suggest that an organspecific abnormality of Treg in the skin underscores the importance of analyzing Treg in the affected tissue. Such a local process might give insight into the pathogenic mechanisms of CLE and differs from a global peripheral dysfunction as reported for patients with a systemic manifestation of the disease.

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“…Whereas CCR7-deficient naive-like Treg fail to recirculate through LN, resulting in an almost complete abolishment of their ability to inhibit the proliferation of naive T cells at this site, effector/memory-like Treg from CCR7 -/-mice display an increased accumulation in inflamed sites, which was accompanied by an enhanced suppression of the inflammatory reaction. CCR7 expression was predominantly observed on naive-like Treg [3,5,6,11,[31][32][33][34] and CCR7-expressing CD62L high CD25 + CD4 + Treg were found to be very efficient in preventing the development of autoimmunity [5] or in suppressing graft-versus-host disease [35,36]. It was suggested that Treg recirculation through LN mediated by CCR7 and CD62L is a prerequisite to suppress priming of autoreactive effector cells.…”

Section: Discussionmentioning

confidence: 99%

“…by use of the marker a E (CD103), into a lineage or differentiation stage of natural, naive-like a E -CD25 + Treg and into that of a E + Treg (either CD25 + or CD25 -) with the phenotype of effector/memory cells [3], a distinction that might partially relate to the differentiation into natural and adaptive Treg [4]. Whereas naive-like Treg express molecules including CD62L and CC chemokine receptor 7 (CCR7), allowing recirculation through lymphoid tissues [3,5,6], effector/memory-like Treg display a high chemokine and homing receptor versatility and efficiently migrate into peripheral tissues and inflamed sites [3,5,[7][8][9][10][11][12]. These findings prompted us to propose a model of division of labor that is largely based on the differential migration behavior of naiveand effector/memory-like Treg subsets [2,3].…”

Section: Introductionmentioning

confidence: 99%

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

et al. 2007

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Foxp3 + CD25 + CD4 + Treg play a fundamental role in the maintenance of self tolerance and the control of inflammatory reactions. Previous data demonstrated a division of labor between naive-and effector/memory-like Treg subsets, which is largely based on their lymph node-recirculating and inflammation-seeking migration behavior, respectively. The chemokine receptor CCR7 is expressed on both types of Treg subsets, albeit at different levels. Whether it fulfills similar or distinct roles in these subsets has not been studied so far. We here show that the recirculation of naive-like Treg through LN and, to some extent, the gut is dependent on CCR7. Lack of CCR7 not only prevents recirculation, but also almost completely abolishes the ability of naive-like Treg to control the priming phase of an immune response. In contrast, CCR7 deficiency in effector/memory-like Treg promotes their accumulation in inflamed sites, compatible with a role of CCR7 for exit from the tissue. Local Treg accumulation was accompanied by an enhanced suppression of inflammation. Together, our findings provide conclusive evidence that CCR7 expression on Treg differentially controls in vivo function of the naive-and effector/memory-like subsets.

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A peripheral circulating compartment of natural naive CD4+ Tregs

Cited by 268 publications

References 45 publications

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

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A peripheral circulating compartment of natural naive CD4+ Tregs

Cited by 268 publications

References 45 publications

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

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Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation