The major histocompatibility complex (MHC)-dependent presentation of processed tissue-specific self-antigens can contribute to either peripheral (extrathymic) tolerance or the differentiation of autoreactive T cells. Here, we have studied the MHC class II molecule presentation of gastric parietal cell (PC)-specific H⁺/K⁺-ATPase, which induces a destructive autoimmune gastritis in BALB/c mice lacking CD4⁺ CD25⁺ regulatory T cells. Immunofluorescence microscopy showed physical association of CD11c⁺ dendritic cells (DCs) with PCs in the gastric mucosa. H⁺/K⁺-ATPase protein was found within vesicular compartments of a few CD11c⁺ DCs only in the draining gastric lymph node (LN) and these antigen-containing DCs increased markedly in number with the onset of tissue destruction in autoimmune animals. Both CD8α^hi and CD8α^lo gastric DCs, but not peripheral or mesenteric DCs, showed evidence of constitutive in vivo processing and presentation of H⁺/K⁺-ATPase. These data provide direct support for a widely held model of local tissue antigen uptake and trafficking by DCs in normal animals and demonstrate that DCs in the draining LN can present a tissue-specific self-antigen under noninflammatory conditions without fully deleting autoreactive T cells or inducing active autoimmunity.