Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T Cells into alloantigen-specific and allograft protective foxp3+ regulatory T cells

Hua Yang, Elaine Y. Cheng, Vijay K. Sharma, Mila Lagman, Christina Chang, Ping Song, Ruchuang Ding, Thangamani Muthukumar, Manikkam Suthanthiran

Research output: Contribution to journalArticle

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Abstract

Background: Naturally occurring, thymic-derived Foxp3+CD25+CD4+ regulatory T cells (nTregs) are pivotal for the maintenance of self-tolerance. nTregs, however, are sparse and lack alloantigen specificity, and these properties pose challenges for their use in clinical transplantation. Methods: We established mixed leukocyte reaction (MLR) with dendritic cells (DCs) as stimulators and CD4+ T cells as responders and supplemented the MLR with IL-2 and TGF-β1 and investigated whether DCs+IL-2+TGF-β1 differentiate the polyclonal CD4+ cells into alloantigen-specific and allograft protective Tregs. Results: We found a greater than a 10-fold increase in Foxp3+CD25+ subpopulation (P<0.01) following stimulation of BALB/c CD4+ cells with C57BL/6 (B6) CD11c+ DCs+IL-2+TGF-β1 in the MLR. Levels of TGF-β1 messenger RNA (mRNA) (P=0.01) and the ratios of TGF-β1 mRNA to granzyme B mRNA (P=0.0003) and Foxp3 mRNA to granzyme B mRNA (P<0.01) were higher in alloantigen-induced Tregs (alloTregs) compared with nTregs. alloTregs suppressed MLR at a 16:1 responder to suppressor ratio, whereas nTregs suppressed at 4:1. Suppression by alloTregs was alloantigen specific and was observed at the level of responder cells and at the level of stimulator cells. In a fully H-2-mismatched, nonlymphopenic, immunocompetent mouse islet transplantation model, alloTregs but not nTregs prolonged survival of islet allografts without any other immunosuppressive therapy (P=0.0003), and the protection was alloantigen specific. Conclusions: A combination of CD11c+ DCs, IL-2, and TGF-β1 may help differentiate naive, high abundant CD4+ T into alloantigen-specific and allograft protective Foxp3+Tregs.

Original languageEnglish
Pages (from-to)580-588
Number of pages9
JournalTransplantation
Volume93
Issue number6
DOIs
Publication statusPublished - 27 Mar 2012
Externally publishedYes

Fingerprint

Isoantigens
Regulatory T-Lymphocytes
Dendritic Cells
Interleukin-2
Allografts
T-Lymphocytes
Mixed Lymphocyte Culture Test
Messenger RNA
Granzymes
Self Tolerance
Islets of Langerhans Transplantation
Immunosuppressive Agents
Transplantation

Keywords

  • Dendritic cells
  • Foxp3
  • Islet cell transplantation
  • Regulatory T cells

ASJC Scopus subject areas

  • Transplantation

Cite this

Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T Cells into alloantigen-specific and allograft protective foxp3+ regulatory T cells. / Yang, Hua; Cheng, Elaine Y.; Sharma, Vijay K.; Lagman, Mila; Chang, Christina; Song, Ping; Ding, Ruchuang; Muthukumar, Thangamani; Suthanthiran, Manikkam.

In: Transplantation, Vol. 93, No. 6, 27.03.2012, p. 580-588.

Research output: Contribution to journalArticle

Yang, Hua ; Cheng, Elaine Y. ; Sharma, Vijay K. ; Lagman, Mila ; Chang, Christina ; Song, Ping ; Ding, Ruchuang ; Muthukumar, Thangamani ; Suthanthiran, Manikkam. / Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T Cells into alloantigen-specific and allograft protective foxp3+ regulatory T cells. In: Transplantation. 2012 ; Vol. 93, No. 6. pp. 580-588.
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abstract = "Background: Naturally occurring, thymic-derived Foxp3+CD25+CD4+ regulatory T cells (nTregs) are pivotal for the maintenance of self-tolerance. nTregs, however, are sparse and lack alloantigen specificity, and these properties pose challenges for their use in clinical transplantation. Methods: We established mixed leukocyte reaction (MLR) with dendritic cells (DCs) as stimulators and CD4+ T cells as responders and supplemented the MLR with IL-2 and TGF-β1 and investigated whether DCs+IL-2+TGF-β1 differentiate the polyclonal CD4+ cells into alloantigen-specific and allograft protective Tregs. Results: We found a greater than a 10-fold increase in Foxp3+CD25+ subpopulation (P<0.01) following stimulation of BALB/c CD4+ cells with C57BL/6 (B6) CD11c+ DCs+IL-2+TGF-β1 in the MLR. Levels of TGF-β1 messenger RNA (mRNA) (P=0.01) and the ratios of TGF-β1 mRNA to granzyme B mRNA (P=0.0003) and Foxp3 mRNA to granzyme B mRNA (P<0.01) were higher in alloantigen-induced Tregs (alloTregs) compared with nTregs. alloTregs suppressed MLR at a 16:1 responder to suppressor ratio, whereas nTregs suppressed at 4:1. Suppression by alloTregs was alloantigen specific and was observed at the level of responder cells and at the level of stimulator cells. In a fully H-2-mismatched, nonlymphopenic, immunocompetent mouse islet transplantation model, alloTregs but not nTregs prolonged survival of islet allografts without any other immunosuppressive therapy (P=0.0003), and the protection was alloantigen specific. Conclusions: A combination of CD11c+ DCs, IL-2, and TGF-β1 may help differentiate naive, high abundant CD4+ T into alloantigen-specific and allograft protective Foxp3+Tregs.",
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T1 - Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T Cells into alloantigen-specific and allograft protective foxp3+ regulatory T cells

AU - Yang, Hua

AU - Cheng, Elaine Y.

AU - Sharma, Vijay K.

AU - Lagman, Mila

AU - Chang, Christina

AU - Song, Ping

AU - Ding, Ruchuang

AU - Muthukumar, Thangamani

AU - Suthanthiran, Manikkam

PY - 2012/3/27

Y1 - 2012/3/27

N2 - Background: Naturally occurring, thymic-derived Foxp3+CD25+CD4+ regulatory T cells (nTregs) are pivotal for the maintenance of self-tolerance. nTregs, however, are sparse and lack alloantigen specificity, and these properties pose challenges for their use in clinical transplantation. Methods: We established mixed leukocyte reaction (MLR) with dendritic cells (DCs) as stimulators and CD4+ T cells as responders and supplemented the MLR with IL-2 and TGF-β1 and investigated whether DCs+IL-2+TGF-β1 differentiate the polyclonal CD4+ cells into alloantigen-specific and allograft protective Tregs. Results: We found a greater than a 10-fold increase in Foxp3+CD25+ subpopulation (P<0.01) following stimulation of BALB/c CD4+ cells with C57BL/6 (B6) CD11c+ DCs+IL-2+TGF-β1 in the MLR. Levels of TGF-β1 messenger RNA (mRNA) (P=0.01) and the ratios of TGF-β1 mRNA to granzyme B mRNA (P=0.0003) and Foxp3 mRNA to granzyme B mRNA (P<0.01) were higher in alloantigen-induced Tregs (alloTregs) compared with nTregs. alloTregs suppressed MLR at a 16:1 responder to suppressor ratio, whereas nTregs suppressed at 4:1. Suppression by alloTregs was alloantigen specific and was observed at the level of responder cells and at the level of stimulator cells. In a fully H-2-mismatched, nonlymphopenic, immunocompetent mouse islet transplantation model, alloTregs but not nTregs prolonged survival of islet allografts without any other immunosuppressive therapy (P=0.0003), and the protection was alloantigen specific. Conclusions: A combination of CD11c+ DCs, IL-2, and TGF-β1 may help differentiate naive, high abundant CD4+ T into alloantigen-specific and allograft protective Foxp3+Tregs.

AB - Background: Naturally occurring, thymic-derived Foxp3+CD25+CD4+ regulatory T cells (nTregs) are pivotal for the maintenance of self-tolerance. nTregs, however, are sparse and lack alloantigen specificity, and these properties pose challenges for their use in clinical transplantation. Methods: We established mixed leukocyte reaction (MLR) with dendritic cells (DCs) as stimulators and CD4+ T cells as responders and supplemented the MLR with IL-2 and TGF-β1 and investigated whether DCs+IL-2+TGF-β1 differentiate the polyclonal CD4+ cells into alloantigen-specific and allograft protective Tregs. Results: We found a greater than a 10-fold increase in Foxp3+CD25+ subpopulation (P<0.01) following stimulation of BALB/c CD4+ cells with C57BL/6 (B6) CD11c+ DCs+IL-2+TGF-β1 in the MLR. Levels of TGF-β1 messenger RNA (mRNA) (P=0.01) and the ratios of TGF-β1 mRNA to granzyme B mRNA (P=0.0003) and Foxp3 mRNA to granzyme B mRNA (P<0.01) were higher in alloantigen-induced Tregs (alloTregs) compared with nTregs. alloTregs suppressed MLR at a 16:1 responder to suppressor ratio, whereas nTregs suppressed at 4:1. Suppression by alloTregs was alloantigen specific and was observed at the level of responder cells and at the level of stimulator cells. In a fully H-2-mismatched, nonlymphopenic, immunocompetent mouse islet transplantation model, alloTregs but not nTregs prolonged survival of islet allografts without any other immunosuppressive therapy (P=0.0003), and the protection was alloantigen specific. Conclusions: A combination of CD11c+ DCs, IL-2, and TGF-β1 may help differentiate naive, high abundant CD4+ T into alloantigen-specific and allograft protective Foxp3+Tregs.

KW - Dendritic cells

KW - Foxp3

KW - Islet cell transplantation

KW - Regulatory T cells

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