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A Role for a Melanosome Transport Signal in Accessing the MHC Class II Presentation Pathway and in Eliciting CD4⁺ T Cell Responses¹

Siqun Wang^2,*,, Shirley Bartido^2,*, George Yang^*,¶, Jie Qin^*,¶, Yoichi Moroi^*, Katherine S. Panageas^§, Jonathan J. Lewis^*, and Alan N. Houghton^3,*,,¶

^* Swim Across America Laboratory, Departments of Surgery, Medicine, and ^§ Biostatistics and Epidemiology, and ^¶ Sloan-Kettering Division, Cornell University Graduate School of Medical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Melanosomal membrane proteins are frequently recognized by the immune system of patients with melanoma and vitiligo. Melanosomal glycoproteins are transported to melanosomes by a dileucine-based melanosomal transport signal (MTS). To investigate whether this sorting signal could be involved in presentation of melanosome membrane proteins to the immune system, we devised a fusion construct containing the MTS from the mouse brown locus product gp75/tyrosinase-related protein-1 and full-length OVA as a reporter Ag. The fusion protein was expressed as an intracellular membrane protein, sorted to the endocytic pathway, processed, and presented by class II MHC molecules. DNA immunization with this construct elicited CD4⁺ T cell proliferative responses in vivo. Ag presentation and T cell responses in vitro and in vivo required a functional MTS. Mutations of either the upstream leucine in MTS or elimination of the entire MTS negated in vitro Ag presentation and in vivo T cell responses. In a mouse melanoma model, DNA immunization with MTS constructs protected mice from tumor challenge in a CD4⁺ T cell-dependent manner, but complete deletion of MTS decreased tumor rejection. Therefore, MTS can target epitopes to the endocytic pathway leading to presentation by class II MHC molecules to helper T cells.

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