Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma
Katelyn T. Byrne, … , Edward J. Usherwood, Mary Jo Turk
Katelyn T. Byrne, … , Edward J. Usherwood, Mary Jo Turk
Published April 11, 2011
Citation Information: J Clin Invest. 2011;121(5):1797-1809. https://doi.org/10.1172/JCI44849.
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Research Article Oncology

Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma

Abstract

A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8+ T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4+ T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8+ memory T cells specific for shared melanoma/melanocyte antigens. CD8+ T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8+ T cell immunity to melanoma. Vitiligo-associated memory CD8+ T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer.

Authors

Katelyn T. Byrne, Anik L. Côté, Peisheng Zhang, Shannon M. Steinberg, Yanxia Guo, Rameeza Allie, Weijun Zhang, Marc S. Ernstoff, Edward J. Usherwood, Mary Jo Turk

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Figure 4

Restoration of melanocyte antigen to T cells primed in Wsh mice rescues robust effector memory T cell populations.

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Restoration of melanocyte antigen to T cells primed in Wsh mice rescues ...
Wsh mice received 104 naive Thy1.1+ pmel cells 1 day before treatment as in Figure 1A. (A and B) Starting on the day of surgery, mice received 40 μg of mouse gp100–expressing plasmid, or empty vector control i.m., once weekly for 30 days. Thirty days after surgery, (A) the proportion of pmel cells among total CD8+ cells in each organ and (B) expression of CD62L on CD8+ pmel or host CD44hi cells were determined by flow cytometry. Histogram depicts data from 1 representative gp100-treated mouse; fewer than 50 pmel events were obtained for 7 of 8 mice treated with empty vector. (C and D) Total CD8+ cells were harvested from inguinal lymph nodes and spleens of Wsh mice on day 12 and adoptively transferred into the indicated recipients that had been pretreated as in Figure 1A. Thirty days after surgery/adoptive transfer, recipients were analyzed for (C) proportion of pmel cells among total CD8+ cells and (D) CD62L expression on CD8+ pmel or host CD44hi cells in inguinal lymph nodes. Histogram depicts data from 1 representative vitiligo recipient; fewer than 50 pmel events were obtained for each of the Wsh recipients. Dot plots in A and C depict data from representative mice. Data represent 2 combined experiments with similar results; symbols represent individual mice, and horizontal lines represent averages. Statistically significant differences were assessed by t test.