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Deletional Self-Tolerance to a Melanocyte/Melanoma Antigen Derived from Tyrosinase Is Mediated by a Radio-Resistant Cell in Peripheral and Mesenteric Lymph Nodes¹

Lisa A. Nichols^*, Yiming Chen^2,*, Teresa A. Colella^*, Clare L. Bennett, Björn E. Clausen and Victor H. Engelhard^3,*

^* Department of Microbiology and Carter Immunology Center, University of Virginia Health System, Charlottesville, VA 22908; and Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Self-tolerance to melanocyte differentiation Ags limits the ability to generate therapeutic antimelanoma responses. However, the mechanisms responsible for CD8 T cell tolerance to these Ags are unknown. We have used a newly generated TCR-transgenic mouse to establish the basis of tolerance to one such Ag from tyrosinase. Despite expression of tyrosinase transcripts in the thymus, central deletion does not shape the tyrosinase-specific CD8 T cell repertoire. We demonstrate that this endogenously expressed melanocyte Ag is constitutively presented in both peripheral and mesenteric lymph nodes, leading to abortive activation and deletion of tyrosinase-specific CD8 T cells. Importantly, this Ag is not presented by either radio-sensitive dendritic cells, or by radio-resistant Langerhans cells. Thus, for this endogenous Ag, cross-tolerization does not appear to be an operative mechanism. Instead, we find radioresistant tyrosinase mRNA expression in lymphoid compartments where CD8 T cell deletion occurs. This suggests that direct presentation of tyrosinase by radio-resistant lymph node resident cells is entirely responsible for tolerance to this endogenous melanocyte differentiation Ag.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants CA78400 and AI059996 from the National Institutes of Health (NIH; to V.H.E.). L.A.N. was supported by NIH Training Grants A107486 and GM08136. B.E.C. is a fellow of the Landsteiner Foundation for Blood Transfusion Research (LSBR 0414).

² Current address: Department of Thoracic & Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77054.

³ Address correspondence and reprint requests to Dr. Victor H. Engelhard, Carter Immunology Center, University of Virginia, Box 801386, Charlottesville, VA 22908-1386. E-mail address: vhe{at}virginia.edu

⁴ Abbreviations used in this paper: MDP, melanocyte differentiation protein; DC, dendritic cell; LN, lymph node; mTEC, medullary thymic epithelial cell; BM, bone marrow; LC, Langerhans cell; pLN, peripheral LN; mesLN, mesenteric LN; Ct, cycle threshold; SP, single positive; mTyrVac, recombinant vaccinia expressing full-length murine tyrosinase; DT, diphtheria toxin.

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