A new lineage of effector/memory CD4+ T cells has been identified whose signature products are IL‐17 cytokines and whose differentiation requires the nuclear receptor, RORγt. These Th17 cells are critical effectors in mouse models of autoimmune disease. We have analyzed the association between chemokine receptor expression and IL‐17 production for human T cells. Activating cord blood (naïve) CD4+ T cells under conditions driving Th17 differentiation led to preferential induction of CCR6, CCR9 and CXCR6. Despite these data, we found no strong correlation between the production of IL‐17 and expression of CCR9 or CXCR6. By contrast, virtually all IL‐17‐producing CD4+ T cells, either made in our in vitro or found in peripheral blood, expressed CCR6. Compared with CD4+CD45RO+CCR6− cells, CD4+CD45RO+CCR6+ cells contained at least 100‐fold more IL‐17A mRNA and secreted 100‐fold more IL‐17 protein. The CCR6+ cells showed a similar enrichment in mRNA for RORγt. CCR6 was likewise expressed on all IL‐17‐producing CD8+ PBL. CCR6 has been associated with the trafficking of T, B, and dendritic cells to epithelial sites, but has not been linked to a specific T cell phenotype. Our data reveal a fundamental feature of IL‐17‐producing human T cells and a novel role for CCR6, suggesting both new directions for investigating IL‐17‐related immune responses and possible targets for preventing inflammatory injury. Research support: NIAID, NIH

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Defective lysosomal acidification contributes to virtually all lysosomal storage disorders (LSDs) and to common neurodegenerative diseases like Alzheimer's and Parkinson's. Despite its fundamental importance, the mechanism(s) underlying this defect remains unclear. The v-ATPase, a multisubunit protein complex composed of cytosolic V1-sector and lysosomal membrane-anchored V0-sector, regulates lysosomal acidification. Mutations in the CLN1 gene, encoding PPT1, cause a devastating neurodegenerative LSD, INCL. Here we report that in Cln1−/− mice, which mimic INCL, reduced v-ATPase activity correlates with elevated lysosomal pH. Moreover, v-ATPase subunit a1 of the V0 sector (V0a1) requires palmitoylation for interacting with adaptor protein-2 (AP-2) and AP-3, respectively, for trafficking to the lysosomal membrane. Notably, treatment of Cln1−/− mice with a thioesterase (Ppt1)-mimetic, NtBuHA, ameliorated this defect. Our findings reveal an unanticipated role of Cln1 in regulating lysosomal targeting of V0a1 and suggest that varying factors adversely affecting v-ATPase function dysregulate lysosomal acidification in other LSDs and common neurodegenerative diseases.