TY - JOUR
T1 - GILT accelerates autoimmunity to the melanoma antigen tyrosinase-related protein 1
AU - Rausch, Matthew P.
AU - Irvine, Kari R.
AU - Antony, Paul A.
AU - Restifo, Nicholas P.
AU - Cresswell, Peter
AU - Hastings, K. Taraszka
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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. γ-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.
AB - 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. γ-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.
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U2 - 10.4049/jimmunol.1000945
DO - 10.4049/jimmunol.1000945
M3 - Article
C2 - 20668223
AN - SCOPUS:78049356430
SN - 0022-1767
VL - 185
SP - 2828
EP - 2835
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -