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.
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: K
authors.initials: K
authors.lastname: Cunnusamy
authors.forename: J Y
authors.initials: JY
authors.lastname: Niederkorn
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D003315:Cornea / Q000276:immunology / Q000473:pathology; D016039:Corneal Transplantation / Q000379:methods*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D007107:Immune System; D007371:Interferon-gamma / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D018418:Th2 Cells
chemical_list: D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D015778:Minor Histocompatibility Antigens; D007371:Interferon-gamma
keywords: Cornea; IFN-γ; Tregs; immune privilege; keratoplasty