Aire deficiency promotes TRP-1-specific immune rejection of melanoma.
The thymic transcription factor autoimmune regulator (Aire) prevents autoimmunity in part by promoting expression of tissue-specific self-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to cancer and provide insights into how such responses might be triggered. In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1-specific T cells without affecting thymic numbers of regulatory T cells. Aire-deficient mice displayed elevated T-cell immune responses that were associated with suppression of melanoma outgrowth. Furthermore, transplantation of Aire-deficient thymic stroma was sufficient to confer more effective immune rejection of melanoma in an otherwise Aire wild-type host. Together, our work showed how Aire deficiency can enhance immune responses against melanoma and how manipulating TRP-1-specific T-cell negative selection may offer a logical strategy to enhance immune rejection of melanoma.
Department of Pediatrics and Microbiology/Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Meng-Lei
ML
Zhu
Anil
A
Nagavalli
Maureen A
MA
Su
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007108:Immune Tolerance; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D010088:Oxidoreductases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000378:metabolism / Q000637:transplantation; D014157:Transcription Factors / Q000502:physiology*; D000096927:AIRE Protein
D001324:Autoantigens; D008562:Membrane Glycoproteins; D010088:Oxidoreductases; D012333:RNA, Messenger; D014157:Transcription Factors; D000096927:AIRE Protein; C079621:Tyrp1 protein, mouse