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Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation.

Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G - Front Immunol (2015)

Bottom Line: The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells.Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application.This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK.

ABSTRACT
Regulatory T cells (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone-marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid-organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy. Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of Treg suppression. (A) Disruption of metabolic pathways. The ectoenzymes CD39 and CD73, expressed on Tregs, result in the metabolism of ATP to AMP and in turn producing the immunoregulatory purine, adenosine. Tregs have also been found to express high levels of intracellular cAMP. This is transferred to T effector cells through gap junctions, which leads to the upregulation of ICER and in turn the inhibition of NFAT and Il-2 transcription leading to apoptosis by IL-2 deprivation. (B) Modulation of APC maturation and function. The interaction of CTLA-4 on Tregs with its ligand CD80/86 on APCs delivers a negative signal for T cell activation. CTLA-4’s mechanism of action is varied including the capture of its APC-expressed ligands and subsequent trans-endocytosis and also the upregulation of IDO and the generation of kynurenines. (C) Anti-inflammatory cytokine production. The secretion of anti-inflammatory cytokines, such as IL-10, IL-35, and TGF-β, has been linked with inhibition of T cell activation in vivo. (D) Induction of apoptosis. Tregs have the capacity to directly induce apoptosis via granzyme A/B and perforin, TRAIL, the Fas/Fas-ligand pathway, the galectin-9/TIM-3 pathway, or the production of galectin-1. Abbreviations: APC, antigen presenting cell; AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CD, cluster differentiation; CTLA-4-cytotoxic T lymphocyte antigen-4; DC, dendritic cells; ICER, inducible cAMP early repressor, IDO, indoleamine 2,3-dioxygenase IL, interleukin; NFAT, nuclear factor of activated T cells; TGF-β, transforming growth factor-β; TIM-3, T cell immunoglobulin and mucin domain-3; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; Treg, regulatory T cells.
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Figure 2: Mechanisms of Treg suppression. (A) Disruption of metabolic pathways. The ectoenzymes CD39 and CD73, expressed on Tregs, result in the metabolism of ATP to AMP and in turn producing the immunoregulatory purine, adenosine. Tregs have also been found to express high levels of intracellular cAMP. This is transferred to T effector cells through gap junctions, which leads to the upregulation of ICER and in turn the inhibition of NFAT and Il-2 transcription leading to apoptosis by IL-2 deprivation. (B) Modulation of APC maturation and function. The interaction of CTLA-4 on Tregs with its ligand CD80/86 on APCs delivers a negative signal for T cell activation. CTLA-4’s mechanism of action is varied including the capture of its APC-expressed ligands and subsequent trans-endocytosis and also the upregulation of IDO and the generation of kynurenines. (C) Anti-inflammatory cytokine production. The secretion of anti-inflammatory cytokines, such as IL-10, IL-35, and TGF-β, has been linked with inhibition of T cell activation in vivo. (D) Induction of apoptosis. Tregs have the capacity to directly induce apoptosis via granzyme A/B and perforin, TRAIL, the Fas/Fas-ligand pathway, the galectin-9/TIM-3 pathway, or the production of galectin-1. Abbreviations: APC, antigen presenting cell; AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CD, cluster differentiation; CTLA-4-cytotoxic T lymphocyte antigen-4; DC, dendritic cells; ICER, inducible cAMP early repressor, IDO, indoleamine 2,3-dioxygenase IL, interleukin; NFAT, nuclear factor of activated T cells; TGF-β, transforming growth factor-β; TIM-3, T cell immunoglobulin and mucin domain-3; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; Treg, regulatory T cells.

Mentions: Additionally, following the recent discovery of naïve suppressive FOXP3+ cells (CD45RA+) present in the cord blood and in adult blood, and FOXP3+ cells, which express a memory-like phenotype (CD45RA−), it has been proposed that three phenotypically and functionally distinct sub-populations based on the differential expression of CD25, FOXP3, and CD45RA can be defined: population I (CD25++FOXP3+CD45RA+) classified as resting Tregs, population II (CD25+++FOXP3hiCD45RA−) termed activated Tregs, and population III (CD25++FOXP3+CD45RA−), which was proposed to consist of non-suppressive FOXP3lo cells (19). Further analysis of the three populations by Miyara et al. revealed that population I and II were both able to suppress in vitro with population II displaying a higher expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a mechanism proposed for Treg suppressor function (Figure 2), yet were more prone to apoptosis following exertion of their suppressive function. Population III, however, was shown to be non-suppressive in vitro (19).


Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation.

Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G - Front Immunol (2015)

Mechanisms of Treg suppression. (A) Disruption of metabolic pathways. The ectoenzymes CD39 and CD73, expressed on Tregs, result in the metabolism of ATP to AMP and in turn producing the immunoregulatory purine, adenosine. Tregs have also been found to express high levels of intracellular cAMP. This is transferred to T effector cells through gap junctions, which leads to the upregulation of ICER and in turn the inhibition of NFAT and Il-2 transcription leading to apoptosis by IL-2 deprivation. (B) Modulation of APC maturation and function. The interaction of CTLA-4 on Tregs with its ligand CD80/86 on APCs delivers a negative signal for T cell activation. CTLA-4’s mechanism of action is varied including the capture of its APC-expressed ligands and subsequent trans-endocytosis and also the upregulation of IDO and the generation of kynurenines. (C) Anti-inflammatory cytokine production. The secretion of anti-inflammatory cytokines, such as IL-10, IL-35, and TGF-β, has been linked with inhibition of T cell activation in vivo. (D) Induction of apoptosis. Tregs have the capacity to directly induce apoptosis via granzyme A/B and perforin, TRAIL, the Fas/Fas-ligand pathway, the galectin-9/TIM-3 pathway, or the production of galectin-1. Abbreviations: APC, antigen presenting cell; AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CD, cluster differentiation; CTLA-4-cytotoxic T lymphocyte antigen-4; DC, dendritic cells; ICER, inducible cAMP early repressor, IDO, indoleamine 2,3-dioxygenase IL, interleukin; NFAT, nuclear factor of activated T cells; TGF-β, transforming growth factor-β; TIM-3, T cell immunoglobulin and mucin domain-3; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; Treg, regulatory T cells.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4553385&req=5

Figure 2: Mechanisms of Treg suppression. (A) Disruption of metabolic pathways. The ectoenzymes CD39 and CD73, expressed on Tregs, result in the metabolism of ATP to AMP and in turn producing the immunoregulatory purine, adenosine. Tregs have also been found to express high levels of intracellular cAMP. This is transferred to T effector cells through gap junctions, which leads to the upregulation of ICER and in turn the inhibition of NFAT and Il-2 transcription leading to apoptosis by IL-2 deprivation. (B) Modulation of APC maturation and function. The interaction of CTLA-4 on Tregs with its ligand CD80/86 on APCs delivers a negative signal for T cell activation. CTLA-4’s mechanism of action is varied including the capture of its APC-expressed ligands and subsequent trans-endocytosis and also the upregulation of IDO and the generation of kynurenines. (C) Anti-inflammatory cytokine production. The secretion of anti-inflammatory cytokines, such as IL-10, IL-35, and TGF-β, has been linked with inhibition of T cell activation in vivo. (D) Induction of apoptosis. Tregs have the capacity to directly induce apoptosis via granzyme A/B and perforin, TRAIL, the Fas/Fas-ligand pathway, the galectin-9/TIM-3 pathway, or the production of galectin-1. Abbreviations: APC, antigen presenting cell; AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CD, cluster differentiation; CTLA-4-cytotoxic T lymphocyte antigen-4; DC, dendritic cells; ICER, inducible cAMP early repressor, IDO, indoleamine 2,3-dioxygenase IL, interleukin; NFAT, nuclear factor of activated T cells; TGF-β, transforming growth factor-β; TIM-3, T cell immunoglobulin and mucin domain-3; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; Treg, regulatory T cells.
Mentions: Additionally, following the recent discovery of naïve suppressive FOXP3+ cells (CD45RA+) present in the cord blood and in adult blood, and FOXP3+ cells, which express a memory-like phenotype (CD45RA−), it has been proposed that three phenotypically and functionally distinct sub-populations based on the differential expression of CD25, FOXP3, and CD45RA can be defined: population I (CD25++FOXP3+CD45RA+) classified as resting Tregs, population II (CD25+++FOXP3hiCD45RA−) termed activated Tregs, and population III (CD25++FOXP3+CD45RA−), which was proposed to consist of non-suppressive FOXP3lo cells (19). Further analysis of the three populations by Miyara et al. revealed that population I and II were both able to suppress in vitro with population II displaying a higher expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a mechanism proposed for Treg suppressor function (Figure 2), yet were more prone to apoptosis following exertion of their suppressive function. Population III, however, was shown to be non-suppressive in vitro (19).

Bottom Line: The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells.Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application.This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK.

ABSTRACT
Regulatory T cells (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone-marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid-organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy. Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

No MeSH data available.


Related in: MedlinePlus