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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

Regulatory T cell populations. Selection of naïve CD4+ T cells and natural Tregs occurs in the thymus. Thymic-derived natural Tregs (tTregs), the main focus of this review, have been reported to express a variety of activation and functional markers as depicted in the diagram. Naïve CD4+ T cells, subsequently, can differentiate into several different T cell subsets: Th1, Th2, Th17, induced Tregs, in the periphery, all heralding distinct immunological roles. These differentiation programs are controlled by different cytokines and each separate CD4+ T cell subset can be identified from their lineage-specific transcription factors responsible for the regulation and maintenance of their individual functions; T-bet (Th1 cells), GATA3 (Th2 cells), RORγt (Th17 cells), FOXP3 (Tregs). Each subset has its own immunological role in vivo: Th1 cells secrete IFNγ, controlling immunity to foreign pathogens. Th2 cells produce various cytokines including: IL-4, IL-5, IL-13, IL-10, which are primarily involved in promoting humoral immunity, protecting against infection. Th17 cells produce predominantly the inflammatory cytokine, IL-17, and play an important role in controlling pathogens especially at environmental surfaces and the cytokine, IL-22. Despite the apparent terminal differentiation of all these cells, they cannot be considered to be committed to one cell fate. Lineage plasticity following differentiation is depicted by the dotted arrows between the cells. This diagram is far from comprehensive; it is most likely that the future will see various changes and additions to this diagram concerning the differentiation of CD4+ T cells. In vitro generation of Tregs in the presence of IL-2 and TGF-β polarizing conditions leads to the development of iTregs. Abbreviations: APC, antigen presenting cells; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FOXP3, forkhead Box P3; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; iTreg, induced Treg; nTreg, natural Treg; pTreg, peripheral Treg; RORγt, retinoid related orphan receptor γ; T-bet, T box transcription factor; TCR, T cell receptor; TGF-β, transforming growth factor-β; Th, T helper cell; Treg, regulatory T cell.
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Figure 1: Regulatory T cell populations. Selection of naïve CD4+ T cells and natural Tregs occurs in the thymus. Thymic-derived natural Tregs (tTregs), the main focus of this review, have been reported to express a variety of activation and functional markers as depicted in the diagram. Naïve CD4+ T cells, subsequently, can differentiate into several different T cell subsets: Th1, Th2, Th17, induced Tregs, in the periphery, all heralding distinct immunological roles. These differentiation programs are controlled by different cytokines and each separate CD4+ T cell subset can be identified from their lineage-specific transcription factors responsible for the regulation and maintenance of their individual functions; T-bet (Th1 cells), GATA3 (Th2 cells), RORγt (Th17 cells), FOXP3 (Tregs). Each subset has its own immunological role in vivo: Th1 cells secrete IFNγ, controlling immunity to foreign pathogens. Th2 cells produce various cytokines including: IL-4, IL-5, IL-13, IL-10, which are primarily involved in promoting humoral immunity, protecting against infection. Th17 cells produce predominantly the inflammatory cytokine, IL-17, and play an important role in controlling pathogens especially at environmental surfaces and the cytokine, IL-22. Despite the apparent terminal differentiation of all these cells, they cannot be considered to be committed to one cell fate. Lineage plasticity following differentiation is depicted by the dotted arrows between the cells. This diagram is far from comprehensive; it is most likely that the future will see various changes and additions to this diagram concerning the differentiation of CD4+ T cells. In vitro generation of Tregs in the presence of IL-2 and TGF-β polarizing conditions leads to the development of iTregs. Abbreviations: APC, antigen presenting cells; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FOXP3, forkhead Box P3; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; iTreg, induced Treg; nTreg, natural Treg; pTreg, peripheral Treg; RORγt, retinoid related orphan receptor γ; T-bet, T box transcription factor; TCR, T cell receptor; TGF-β, transforming growth factor-β; Th, T helper cell; Treg, regulatory T cell.

Mentions: Initially, Tregs were conventionally characterized in accordance with their site of differentiation, namely thymus-derived natural Tregs (tTregs) and peripherally induced Tregs (pTregs), alongside their in vitro counterparts, commonly referred to as iTregs (5) (Figure 1). tTregs, from here on referred to as Tregs, are spawned from negatively selected thymocytes, whereas the conditions favoring the generation of pTregs include suboptimal dendritic cell (DC) activation, sub-immunogenic doses of agonist peptide, mucosal administration of peptide, and antigenic encounter in a pro-tolerogenic environment, such as in the presence of interleukin-10 (IL-10), transforming growth factor-β (TGF-β), interleukin-2 (IL-2), and retinoic acid (6).


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)

Regulatory T cell populations. Selection of naïve CD4+ T cells and natural Tregs occurs in the thymus. Thymic-derived natural Tregs (tTregs), the main focus of this review, have been reported to express a variety of activation and functional markers as depicted in the diagram. Naïve CD4+ T cells, subsequently, can differentiate into several different T cell subsets: Th1, Th2, Th17, induced Tregs, in the periphery, all heralding distinct immunological roles. These differentiation programs are controlled by different cytokines and each separate CD4+ T cell subset can be identified from their lineage-specific transcription factors responsible for the regulation and maintenance of their individual functions; T-bet (Th1 cells), GATA3 (Th2 cells), RORγt (Th17 cells), FOXP3 (Tregs). Each subset has its own immunological role in vivo: Th1 cells secrete IFNγ, controlling immunity to foreign pathogens. Th2 cells produce various cytokines including: IL-4, IL-5, IL-13, IL-10, which are primarily involved in promoting humoral immunity, protecting against infection. Th17 cells produce predominantly the inflammatory cytokine, IL-17, and play an important role in controlling pathogens especially at environmental surfaces and the cytokine, IL-22. Despite the apparent terminal differentiation of all these cells, they cannot be considered to be committed to one cell fate. Lineage plasticity following differentiation is depicted by the dotted arrows between the cells. This diagram is far from comprehensive; it is most likely that the future will see various changes and additions to this diagram concerning the differentiation of CD4+ T cells. In vitro generation of Tregs in the presence of IL-2 and TGF-β polarizing conditions leads to the development of iTregs. Abbreviations: APC, antigen presenting cells; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FOXP3, forkhead Box P3; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; iTreg, induced Treg; nTreg, natural Treg; pTreg, peripheral Treg; RORγt, retinoid related orphan receptor γ; T-bet, T box transcription factor; TCR, T cell receptor; TGF-β, transforming growth factor-β; Th, T helper cell; Treg, regulatory T cell.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Regulatory T cell populations. Selection of naïve CD4+ T cells and natural Tregs occurs in the thymus. Thymic-derived natural Tregs (tTregs), the main focus of this review, have been reported to express a variety of activation and functional markers as depicted in the diagram. Naïve CD4+ T cells, subsequently, can differentiate into several different T cell subsets: Th1, Th2, Th17, induced Tregs, in the periphery, all heralding distinct immunological roles. These differentiation programs are controlled by different cytokines and each separate CD4+ T cell subset can be identified from their lineage-specific transcription factors responsible for the regulation and maintenance of their individual functions; T-bet (Th1 cells), GATA3 (Th2 cells), RORγt (Th17 cells), FOXP3 (Tregs). Each subset has its own immunological role in vivo: Th1 cells secrete IFNγ, controlling immunity to foreign pathogens. Th2 cells produce various cytokines including: IL-4, IL-5, IL-13, IL-10, which are primarily involved in promoting humoral immunity, protecting against infection. Th17 cells produce predominantly the inflammatory cytokine, IL-17, and play an important role in controlling pathogens especially at environmental surfaces and the cytokine, IL-22. Despite the apparent terminal differentiation of all these cells, they cannot be considered to be committed to one cell fate. Lineage plasticity following differentiation is depicted by the dotted arrows between the cells. This diagram is far from comprehensive; it is most likely that the future will see various changes and additions to this diagram concerning the differentiation of CD4+ T cells. In vitro generation of Tregs in the presence of IL-2 and TGF-β polarizing conditions leads to the development of iTregs. Abbreviations: APC, antigen presenting cells; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FOXP3, forkhead Box P3; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; iTreg, induced Treg; nTreg, natural Treg; pTreg, peripheral Treg; RORγt, retinoid related orphan receptor γ; T-bet, T box transcription factor; TCR, T cell receptor; TGF-β, transforming growth factor-β; Th, T helper cell; Treg, regulatory T cell.
Mentions: Initially, Tregs were conventionally characterized in accordance with their site of differentiation, namely thymus-derived natural Tregs (tTregs) and peripherally induced Tregs (pTregs), alongside their in vitro counterparts, commonly referred to as iTregs (5) (Figure 1). tTregs, from here on referred to as Tregs, are spawned from negatively selected thymocytes, whereas the conditions favoring the generation of pTregs include suboptimal dendritic cell (DC) activation, sub-immunogenic doses of agonist peptide, mucosal administration of peptide, and antigenic encounter in a pro-tolerogenic environment, such as in the presence of interleukin-10 (IL-10), transforming growth factor-β (TGF-β), interleukin-2 (IL-2), and retinoic acid (6).

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