The early innate response after Mycobacterium bovis bacille Calmette-Gué rin (BCG) vaccination is poorly characterized but probably decisive for subsequent protective immunity against tuberculosis. Therefore, we vaccinated mice with fluorescent BCG strains in the ear dorsum, as a surrogate of intradermal vaccination in humans. During the first 3 days, we tracked BCG host cells migrating out of the dermis to the auricular draining lymph nodes (ADLNs). Resident skin dendritic cells (DCs) or macrophages did not play a predominant role in early BCG capture and transport to ADLNs. The main BCG host cells rapidly recruited both in the dermis and ADLNs were neutrophils. Fluorescent green or red BCG strains injected into nonoverlapping sites were essentially sheltered by distinct neutrophils in the ADLN capsule, indicating that neutrophils had captured bacilli in peripheral tissue and transported them to the lymphoid organ. Strikingly, we observed BCG-infected neutrophils in the lumen of lymphatic vessels by confocal microscopy on ear dermis. Fluorescencelabeled neutrophils injected into the ears accumulated exclusively into the ipsilateral ADLN capsule after BCG vaccination. IntroductionMycobacterium bovis bacille Calmette-Guérin (BCG) is the only available vaccine against tuberculosis (TB), a major public health problem. Being included in the World Health Organization (WHO) Expanded Program for Immunization, BCG is one of the most widely administered vaccines. It confers high levels of protection against disseminated forms of TB, particularly severe in children, but its efficacy against pulmonary TB in adults is estimated to be only 50% 1 and varies widely among different geographic areas and populations. Thus, more efficient vaccines against TB are urgently needed. There are reasons to believe that such vaccines could be based on BCG. Therefore, a better understanding of the immune response induced by BCG could help in designing better strategies on a rational basis. Today, BCG vaccination is almost exclusively administered intradermally or percutaneously. 2 Early events occurring after BCG vaccination that will have a strong impact on the adaptive immune response are poorly characterized. For example, it is unknown how BCG travels from the injection site to draining lymph nodes (DLNs) and which host cells could be involved in this early process. Mononuclear phagocytes such as epidermal Langerhans cells (LCs), dermal macrophages, and dendritic cells (DCs) are ideally located to capture microorganisms entering skin. Due to their migratory capacity, DCs shuttle pathogens such as HIV 3 or Leishmania major 4 to DLNs. Bacterial dissemination from gut to mesenteric DLNs occurs via infected DCs after ingestion of Salmonella 5 or Listeria. 6 Peripheral tissue DCs are not the only cells at play in bridging innate and acquired immunity to pathogens. Soon after an inflammatory stimulus, blood monocytes are recruited to the injured tissue from which they can migrate via afferent lymph toward DLNs. There, monocytes acquire a DC ...

Mutations in cystic kidney disease genes represent a major genetic cause of end-stage renal disease. However, the molecular cascades controlling the expression of these genes are still poorly understood. Hepatocyte Nuclear Factor 1beta (HNF1beta) is a homeoprotein predominantly expressed in renal, pancreatic and hepatic epithelia. We report here that mice with renal-specific inactivation of HNF1beta develop polycystic kidney disease. We show that renal cyst formation is accompanied by a drastic defect in the transcriptional activation of Umod, Pkhd1 and Pkd2 genes, whose mutations are responsible for distinct cystic kidney syndromes. In vivo chromatin immunoprecipitation experiments demonstrated that HNF1beta binds to several DNA elements in murine Umod, Pkhd1, Pkd2 and Tg737/Polaris genomic sequences. Our results uncover a direct transcriptional hierarchy between HNF1beta and cystic disease genes. Interestingly, most of the identified HNF1beta target gene products colocalize to the primary cilium, a crucial organelle that plays an important role in controlling the proliferation of tubular cells. This may explain the increased proliferation of cystic cells in MODY5 patients carrying autosomal dominant mutations in HNF1beta.

Shigella, the leading cause of bacillary dysentery, uses a type III secretion system (TTSS) to inject proteins into human cells, leading to bacterial invasion and a vigorous inflammatory response. The bacterium is protected against the response by the O antigen of lipopolysaccharide (LPS) on its surface. We show that bacteriophage-encoded glucosylation of Shigella O antigen, the basis of different serotypes, shortens the LPS molecule by around half. This enhances TTSS function without compromising the protective properties of the LPS. Thus, LPS glucosylation promotes bacterial invasion and evasion of innate immunity, which may have contributed to the emergence of serotype diversity in Shigella.