Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes - PubMed (original) (raw)
Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes
Lisa A Nichols et al. J Immunol. 2007.
Abstract
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.
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- CA78400/CA/NCI NIH HHS/United States
- T32 AI007496/AI/NIAID NIH HHS/United States
- R01 AI068836/AI/NIAID NIH HHS/United States
- GM08136/GM/NIGMS NIH HHS/United States
- AI07486/AI/NIAID NIH HHS/United States
- R21 AI059996-02/AI/NIAID NIH HHS/United States
- T32 AI007046/AI/NIAID NIH HHS/United States
- R01 CA078400/CA/NCI NIH HHS/United States
- R01 AI068836-01A2/AI/NIAID NIH HHS/United States
- R21 AI059996/AI/NIAID NIH HHS/United States
- AI059996/AI/NIAID NIH HHS/United States
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