IFN-γ Blocks CD4+CD25+ tregs and abolishes immune privilege of minor histocompatibility mismatched corneal allografts

K. Cunnusamy, J. Y. Niederkorn

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11 Citations (Scopus)

Abstract

Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50% to 90% in both interferon-gamma (IFN-γ) -/- and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility [minor H] antigen-matched, major histocompatibility complex [MHC]-mismatched) and NZB (MHC-matched, minor H antigen-mismatched) corneal allografts - decreasing rejection from 80% to ∼20%. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ T regulatory cells (Tregs) in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival. This study shows that interferon-gamma, which is normally considered a proinflammatory cytokine, is necessary for the generation of T regulatory cells and the survival of MHC-matched, minor histocompatibility-mismatched corneal allografts in mice. See editorial by Evaristo and Alegre on page 3057.

Original languageEnglish (US)
Pages (from-to)3076-3084
Number of pages9
JournalAmerican Journal of Transplantation
Volume13
Issue number12
DOIs
StatePublished - Dec 2013

Fingerprint

Histocompatibility
Interferon-gamma
Allografts
Major Histocompatibility Complex
Regulatory T-Lymphocytes
Minor Histocompatibility Antigens
Cytokines
Th2 Cells
Th1 Cells
Isoantigens
Cell Lineage
Cell Survival
T-Lymphocytes

Keywords

  • Cornea
  • IFN-γ
  • Immune privilege
  • Keratoplasty
  • Tregs

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

Cite this

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title = "IFN-γ Blocks CD4+CD25+ tregs and abolishes immune privilege of minor histocompatibility mismatched corneal allografts",
abstract = "Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50{\%} to 90{\%} in both interferon-gamma (IFN-γ) -/- and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility [minor H] antigen-matched, major histocompatibility complex [MHC]-mismatched) and NZB (MHC-matched, minor H antigen-mismatched) corneal allografts - decreasing rejection from 80{\%} to ∼20{\%}. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ T regulatory cells (Tregs) in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival. This study shows that interferon-gamma, which is normally considered a proinflammatory cytokine, is necessary for the generation of T regulatory cells and the survival of MHC-matched, minor histocompatibility-mismatched corneal allografts in mice. See editorial by Evaristo and Alegre on page 3057.",
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T1 - IFN-γ Blocks CD4+CD25+ tregs and abolishes immune privilege of minor histocompatibility mismatched corneal allografts

AU - Cunnusamy, K.

AU - Niederkorn, J. Y.

PY - 2013/12

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N2 - Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50% to 90% in both interferon-gamma (IFN-γ) -/- and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility [minor H] antigen-matched, major histocompatibility complex [MHC]-mismatched) and NZB (MHC-matched, minor H antigen-mismatched) corneal allografts - decreasing rejection from 80% to ∼20%. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ T regulatory cells (Tregs) in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival. This study shows that interferon-gamma, which is normally considered a proinflammatory cytokine, is necessary for the generation of T regulatory cells and the survival of MHC-matched, minor histocompatibility-mismatched corneal allografts in mice. See editorial by Evaristo and Alegre on page 3057.

AB - Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50% to 90% in both interferon-gamma (IFN-γ) -/- and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility [minor H] antigen-matched, major histocompatibility complex [MHC]-mismatched) and NZB (MHC-matched, minor H antigen-mismatched) corneal allografts - decreasing rejection from 80% to ∼20%. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ T regulatory cells (Tregs) in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival. This study shows that interferon-gamma, which is normally considered a proinflammatory cytokine, is necessary for the generation of T regulatory cells and the survival of MHC-matched, minor histocompatibility-mismatched corneal allografts in mice. See editorial by Evaristo and Alegre on page 3057.

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KW - IFN-γ

KW - Immune privilege

KW - Keratoplasty

KW - Tregs

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