Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells

Mottet, Christian; Uhlig, Holm H.; Powrie, Fiona

doi:10.4049/jimmunol.170.8.3939

Cited by 853 publications

(737 citation statements)

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“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

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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: 99%

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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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“…The regulatory function of these cells has also been tested in different animal models of human disease. In models of colitis, Tregs showed the capacity to prevent and cure gut inflammation 6 . In addition, regulatory cells have been shown to efficiently prevent the development of experimental autoimmune encephalitis in mice, suggesting that these cells might have a potential role in the therapy of human disease 7 .…”

Section: Introductionmentioning

confidence: 99%

In vitro generation of CD4+CD25+ regulatory cells from murine naive T cells

Dominitzki²,

et al. 2007

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“…CD25 + CD4 + T R cells are selected in the thymus by MHC class II-restricted epitopes [4] and have been shown to play a role in regulating mucosal immunity. These T R cells prevent development of murine gastritis after neonatal thymectomy [5,6], are specifically induced in Peyer's patches [7], control induction of transfer colitis [8][9][10] and cure established colitis [11]. CD25 + CD4 + T R are particularly suited for a sentinel role at body surfaces because they express two kinds of receptors, i.e.…”

Section: Introductionmentioning

confidence: 99%

MHC class II‐independent CD25⁺ CD4⁺ CD8α β⁺ α β T cells attenuate CD4⁺ T cell‐induced transfer colitis

2004

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CD4 + § g T cell populations that develop in mice deficient in MHC class II (through 'knockout' of either the A § , or the A g chain of the I-A b molecule) comprise a major 'single-positive' (SP) CD4 + CD8 -subset (60-90%) and a minor 'double-positive' (DP) CD4 + CD8 § g + subset (10-40%). Many DP T cells found in spleen, mesenteric lymph nodes (MLN) and colonic lamina propria (cLP) express CD25, CD103 and Foxp3. Adoptive transfer of SP but not DP T cells from A § -/-or A g -/-B6 mice into congenic RAG -/-hosts induces colitis. Transfer of SP T cells repopulates the host with only SP T cells; transfer of DP T cells repopulates the host with DP and SP T cells. Anti-CD25 antibody treatment of mice transplanted with DP T cells induces severe, lethal colitis; anti-CD25 antibody treatment of mice transplanted with SP T cells further aggravates the course of severe colitis. Hence, regulatory CD25 + T cells within (or developing from) the DP T cell population of MHC class II-deficient mice control the colitogenic potential of CD25 -CD4 + T cells.

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Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells

Cited by 853 publications

References 20 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

In vitro generation of CD4+CD25+ regulatory cells from murine naive T cells

MHC class II‐independent CD25⁺ CD4⁺ CD8α β⁺ α β T cells attenuate CD4⁺ T cell‐induced transfer colitis

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Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells

Cited by 853 publications

References 20 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

In vitro generation of CD4+CD25+ regulatory cells from murine naive T cells

MHC class II‐independent CD25+ CD4+ CD8α β+ α β T cells attenuate CD4+ T cell‐induced transfer colitis

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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

MHC class II‐independent CD25⁺ CD4⁺ CD8α β⁺ α β T cells attenuate CD4⁺ T cell‐induced transfer colitis