Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8α+ conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3−/− mice also lack CD103+CD11b− DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3−/− mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103+CD11b− DCs, with the population of CD103+CD11b+ DCs remaining intact. Batf3−/− mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103+ DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8α+ cDCs and nonlymphoid CD103+ DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ–resident CD8α+ cDCs and nonlymphoid CD103+ DCs.

IntroductionHSC differentiation occurs through a series of intermediate stages, or progenitors, whereby self-renewal capacity is progressively lost and genetic programs limit the development of alternate cell lineages until commitment to a single cell type is reached. The ability to identify distinct progenitor populations via differential surface marker expression has allowed lineage potentials to be determined, and a hierarchical map of lineage restriction to be inferred. The classic model of hematopoietic development suggests that the order in which cells progress though intermediate stages, and thus the order in which developmentally restrictive programs are placed on progenitor cells to limit lineage potential, is fixed. The discovery of the common lymphoid progenitor (CLP), that yields all lymphoid cells, and the common myeloid progenitor, which propagates myeloid, erythroid, and megakaryocytic cells, provided initial evidence for the first division in the hematopoietic developmental hierarchy. 1,2 Subsequent studies, however, led to the identification of progenitors that could not easily be developmentally placed in relation to CLPs, common myeloid progenitors, and other progenitors identified in early studies. For example, in contrast to the lineage potential of common myeloid progenitors, 1,3 lymphoid-primed multipotent progenitors (LMPPs) generate lymphocytes, macrophages, and granulocytes, yet most of these cells lack the ability to generate erythrocytes and megakaryocytes at the clonal level. 4 Similarly, while granulocyte-macrophage progenitors (GMPs) generate granulocytes and macrophages in vivo and in vitro, 1 macrophage-dendritic cell (DC) progenitors (MDPs) generate macrophages and DCs, but not neutrophils. 5 These findings have generated considerable debate as to whether the existence of one progenitor precludes the existence of another progenitor that has partially overlapping developmental potential, whether multiple developmental paths lead to maturity, and whether the mature lineages that ultimately arise from different developmental routes are functionally distinct.The lineage potentials for some of the progenitors mentioned above are still in dispute because of differences in purification strategies and between findings from in vitro and in vivo assays. However, other cases in which a simple hierarchical developmental scheme cannot be applied have been unequivocally proven by multiple groups and complementary approaches. For example, while ϳ 90% of steady-state splenic DCs are thought to be derived from myeloid progenitors, transplantation, genetic tracing, and clonal in vitro assays have all demonstrated that CLPs generate ϳ 10% of the same subsets of DCs in both humans and mice, 6-13 although the continued identification of new DC subsets necessitates the validation of these findings. 14 The DCs derived from common myeloid progenitors and CLPs appear to have similar transcriptional and functional properties. 9,12,13,15 Given that the details of other stages of hematopoietic development ...

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjögren’s syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjögren’s syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjögren’s syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjögren’s syndrome.

Primary Sjögren’s syndrome (pSS) is a complex autoimmune disease characterized by dysfunction of secretory epithelia with only palliative therapy. Patients present with a constellation of symptoms, and the diversity of symptomatic presentation has made it difficult to understand the underlying disease mechanisms. In this study, aggregation of unbiased transcriptome profiling data sets of minor salivary gland biopsies from controls and Sjögren’s syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjögren’s syndrome cases. Stratification of patients based on their clinical characteristics suggested an association between increased LAMP3 expression and the presence of serum autoantibodies including anti-Ro/SSA, anti-La/SSB, anti-nuclear antibodies. In vitro studies demonstrated that LAMP3 expression induces epithelial cell dysfunction leading to apoptosis. Interestingly, LAMP3 expression resulted in the accumulation and release of intracellular TRIM21 (one component of SSA), La (SSB), and α-fodrin protein, common autoantigens in Sjögren’s syndrome, via extracellular vesicles in an apoptosis-independent mechanism. This study defines a clear role for LAMP3 in the initiation of apoptosis and an independent pathway for the extracellular release of known autoantigens leading to the formation of autoantibodies associated with this disease. ClinicalTrials.gov Identifier: NCT00001196, NCT00001390, NCT02327884.