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 2

Vitiligo-affected hosts develop larger CD8+ TEM cell responses compared with unaffected hosts.

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Vitiligo-affected hosts develop larger CD8+ TEM cell responses compared ...
(A) Mice were treated as in Figure 1A. Sixty days after surgery, IFN-γ ELISPOT was performed on CD8+ T cells from vitiligo-affected or unaffected mice (pooled, 6 mice/group), with peptide-pulsed EL4 cells as targets. Data represent average ± SD of 4 replicate wells. Irrel, irrelevant peptide. (B–D) Mice received 104 naive pmel cells 1 day prior to treatment as in Figure 1A. Thirty days after surgery, flow cytometry was performed to detect differences between unaffected and vitiligo-affected mice with regard to (B) the proportion of pmel cells among CD8+ cells and (C) the proportion of CD8+Thy1.1+CD44hi pmel cells with a CD62Llo TEM phenotype. (D) Ninety-days after surgery, the proportion of pmel cells in lymph nodes that produced cytokines upon peptide restimulation. (E and F) Mice received 104 naive Ly5.2+ OT-1 cells 1 day prior to treatment as in Figure 1A, but received B16-OVA tumors. The proportion of OT-1 cells among CD8+ cells 30 days after surgery (E) and the proportion of OT-1 cells with a CD62Lhi TCM phenotype 36 days after surgery (F) were determined. In B–F, flow cytometry plots depict data from representative mice, symbols represent individual mice, and horizontal lines represent averages. Differences between vitiligo-affected and unaffected groups were assessed by t test, with *P < 0.05, **P < 0.01, and ***P < 0.001 and NS denoting P > 0.05. Differences between relevant and irrelevant peptide were significant unless indicated. Each experiment was performed at least twice, with similar results.