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Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T cells into alloantigen-specific and allograft protective Foxp3+ regulatory T cells.
Transplantation 2012; 93(6):580-8T

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.

Authors+Show Affiliations

Division of Nephrology and Hypertension, Department of Medicine, NewYork Presbyterian/Weill Cornell Medical Center, New York, NY, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22270834

Citation

Yang, Hua, et al. "Dendritic Cells With TGF-β1 and IL-2 Differentiate Naive CD4+ T Cells Into Alloantigen-specific and Allograft Protective Foxp3+ Regulatory T Cells." Transplantation, vol. 93, no. 6, 2012, pp. 580-8.
Yang H, Cheng EY, Sharma VK, et al. Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T cells into alloantigen-specific and allograft protective Foxp3+ regulatory T cells. Transplantation. 2012;93(6):580-8.
Yang, H., Cheng, E. Y., Sharma, V. K., Lagman, M., Chang, C., Song, P., ... Suthanthiran, M. (2012). Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T cells into alloantigen-specific and allograft protective Foxp3+ regulatory T cells. Transplantation, 93(6), pp. 580-8. doi:10.1097/TP.0b013e318244dd67.
Yang H, et al. Dendritic Cells With TGF-β1 and IL-2 Differentiate Naive CD4+ T Cells Into Alloantigen-specific and Allograft Protective Foxp3+ Regulatory T Cells. Transplantation. 2012 Mar 27;93(6):580-8. PubMed PMID: 22270834.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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 - 2012/1/25/entrez PY - 2012/1/25/pubmed PY - 2012/5/2/medline SP - 580 EP - 8 JF - Transplantation JO - Transplantation VL - 93 IS - 6 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. SN - 1534-6080 UR - https://www.unboundmedicine.com/medline/citation/22270834/Dendritic_cells_with_TGF_β1_and_IL_2_differentiate_naive_CD4+_T_cells_into_alloantigen_specific_and_allograft_protective_Foxp3+_regulatory_T_cells_ L2 - http://dx.doi.org/10.1097/TP.0b013e318244dd67 DB - PRIME DP - Unbound Medicine ER -