GILT accelerates autoimmunity to the melanoma antigen tyrosinase-related protein 1.
Melanocyte differentiation Ags, including tyrosinase-related protein (TRP) 1, are relevant to both autoimmune skin depigmentation (vitiligo) and tumor immunity, because they are expressed by both benign melanocytes and many malignant melanomas. Melanoma patients generate CD4(+) T cells that specifically recognize these proteins. TRP1 contains internal disulfide bonds and is presented by MHC class II molecules. Gamma-IFN-inducible lysosomal thiol reductase (GILT) facilitates the generation of class II-binding peptides by the endocytic reduction of protein disulfide bonds. We show in this study that GILT is required for efficient MHC class II-restricted processing of a TRP1 epitope in vitro and accelerates the onset of vitiligo in TRP1-specific TCR transgenic mice. The presence of GILT confers a small increase in the percentage of autoreactive T cells with an effector memory phenotype that may contribute to earlier disease onset. The onset of vitiligo is associated with a greater increase in the percentage of autoreactive T cells with an effector memory phenotype. Given that many self and tumor Ags have disulfide bonds and are presented on MHC class II, GILT is likely to be important in the pathogenesis of other CD4(+) T cell-mediated autoimmune diseases and for the development of effective cancer immunotherapy.
Rausch
Matthew P
MP
Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, AZ 85004, USA.
Irvine
Kari R
KR
Antony
Paul A
PA
Restifo
Nicholas P
NP
Cresswell
Peter
P
Hastings
K Taraszka
KT
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis*; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000637:transplantation; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D014820:Vitiligo / Q000201:enzymology / Q000235:genetics / Q000276:immunology*
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors