Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function

Kisha Nandini Sivanathan, Darling M. Rojas-Canales, Christopher M. Hope, Ravi Krishnan, Robert P. Carroll, Stan Gronthos, Shane T. Grey, Patrick T. Coates

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4+CD25highCD127lowFoxP3+ regulatory T cells (iTregs) from PHA-activated CD4+CD25- T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.

LanguageEnglish
Pages2850-2863
Number of pages14
JournalStem Cells
Volume33
Issue number9
DOIs
Publication statusPublished - 1 Sep 2015

Keywords

  • Immunomodulation
  • Interferon-gamma
  • Interleukin-17A
  • Mesenchymal stem cells
  • Regulatory T cells
  • T cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Sivanathan, K. N., Rojas-Canales, D. M., Hope, C. M., Krishnan, R., Carroll, R. P., Gronthos, S., ... Coates, P. T. (2015). Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. Stem Cells, 33(9), 2850-2863. https://doi.org/10.1002/stem.2075
Sivanathan, Kisha Nandini ; Rojas-Canales, Darling M. ; Hope, Christopher M. ; Krishnan, Ravi ; Carroll, Robert P. ; Gronthos, Stan ; Grey, Shane T. ; Coates, Patrick T. / Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. In: Stem Cells. 2015 ; Vol. 33, No. 9. pp. 2850-2863.
@article{5db77929c89b49feb7e191648a451a0d,
title = "Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function",
abstract = "Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4+CD25highCD127lowFoxP3+ regulatory T cells (iTregs) from PHA-activated CD4+CD25- T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.",
keywords = "Immunomodulation, Interferon-gamma, Interleukin-17A, Mesenchymal stem cells, Regulatory T cells, T cells",
author = "Sivanathan, {Kisha Nandini} and Rojas-Canales, {Darling M.} and Hope, {Christopher M.} and Ravi Krishnan and Carroll, {Robert P.} and Stan Gronthos and Grey, {Shane T.} and Coates, {Patrick T.}",
year = "2015",
month = "9",
day = "1",
doi = "10.1002/stem.2075",
language = "English",
volume = "33",
pages = "2850--2863",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "9",

}

Sivanathan, KN, Rojas-Canales, DM, Hope, CM, Krishnan, R, Carroll, RP, Gronthos, S, Grey, ST & Coates, PT 2015, 'Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function', Stem Cells, vol. 33, no. 9, pp. 2850-2863. https://doi.org/10.1002/stem.2075

Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. / Sivanathan, Kisha Nandini; Rojas-Canales, Darling M.; Hope, Christopher M.; Krishnan, Ravi; Carroll, Robert P.; Gronthos, Stan; Grey, Shane T.; Coates, Patrick T.

In: Stem Cells, Vol. 33, No. 9, 01.09.2015, p. 2850-2863.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function

AU - Sivanathan, Kisha Nandini

AU - Rojas-Canales, Darling M.

AU - Hope, Christopher M.

AU - Krishnan, Ravi

AU - Carroll, Robert P.

AU - Gronthos, Stan

AU - Grey, Shane T.

AU - Coates, Patrick T.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4+CD25highCD127lowFoxP3+ regulatory T cells (iTregs) from PHA-activated CD4+CD25- T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.

AB - Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4+CD25highCD127lowFoxP3+ regulatory T cells (iTregs) from PHA-activated CD4+CD25- T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.

KW - Immunomodulation

KW - Interferon-gamma

KW - Interleukin-17A

KW - Mesenchymal stem cells

KW - Regulatory T cells

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=84940467141&partnerID=8YFLogxK

U2 - 10.1002/stem.2075

DO - 10.1002/stem.2075

M3 - Article

VL - 33

SP - 2850

EP - 2863

JO - Stem Cells

T2 - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 9

ER -