Understanding the Functional Properties of Neonatal Dendritic Cells: A Doorway to Enhance Vaccine Effectiveness?

Increased susceptibility to infectious diseases is a hallmark of the neonatal period of life that is generally attributed to a relative immaturity of the immune system. Dendritic cells (DCs) are innate immune sentinels with vital roles in the initiation and orchestration of immune responses, thus, constituting a promising target for promoting neonatal immunity. However, as is the case for other immune cells, neonatal DCs have been suggested to be functionally immature compared to their adult counterparts. Here we review some of the unique aspects of neonatal DCs that shape immune responses in early life and speculate whether the functional properties of neonatal DCs could be exploited or manipulated to promote more effective vaccination in early life

Understanding the Functional Properties of Neonatal Dendritic Cells: A Doorway to Enhance Vaccine Effectiveness?

Increased susceptibility to infectious diseases is a hallmark of the neonatal period of life that is generally attributed to a relative immaturity of the immune system. Dendritic cells (DCs) are innate immune sentinels with vital roles in the initiation and orchestration of immune responses, thus, constituting a promising target for promoting neonatal immunity. However, as is the case for other immune cells, neonatal DCs have been suggested to be functionally immature compared to their adult counterparts. Here we review some of the unique aspects of neonatal DCs that shape immune responses in early life and speculate whether the functional properties of neonatal DCs could be exploited or manipulated to promote more effective vaccination in early life

Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling

Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4(+) T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4(+) T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3(+) regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4(+) T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4(+) T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3(+) Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4(+) T cell subsets by altering their TCR downstream signaling

Clec9a-Mediated Ablation of Conventional Dendritic Cells Suggests a Lymphoid Path to Generating Dendritic Cells In Vivo

Conventional dendritic cells (cDCs) are versatile activators of immune responses that develop as part of the myeloid lineage downstream of hematopoietic stem cells. We have recently shown that in mice precursors of cDCs, but not of other leukocytes, are marked by expression of DNGR-1/CLEC9A. To genetically deplete DNGR-1-expressing cDC precursors and their progeny, we crossed Clec9a-Cre mice to Rosa-lox-STOP-lox-diphtheria toxin (DTA) mice. These mice develop signs of age-dependent myeloproliferative disease, as has been observed in other DC-deficient mouse models. However, despite efficient depletion of cDC progenitors in these mice, cells with phenotypic characteristics of cDCs populate the spleen. These cells are functionally and transcriptionally similar to cDCs in wild type control mice but show somatic rearrangements of Ig-heavy chain genes, characteristic of lymphoid origin cells. Our studies reveal a previously unappreciated developmental heterogeneity of cDCs and suggest that the lymphoid lineage can generate cells with features of cDCs when myeloid cDC progenitors are impaired

Reduced Inflammatory Threshold Indicates Skin Barrier Defect in Transglutaminase 3 Knockout Mice

Recently a transglutaminase 3 knockout (TGM3/KO) mouse was generated that showed impaired hair development, but no gross defects in the epidermal barrier, although increased fragility of isolated corneocytes was demonstrated. Here we investigated the functionality of skin barrier in vivo by percutaneous sensitization to fluorescein-isothiocyanate (FITC) in TGM3/KO (n=64) and C57BL/6 WT mice (n=36). Cutaneous inflammation was evaluated by mouse ear swelling test (MEST), histology, serum IgE levels, and by flow-cytometry from draining lymph nodes. Inflammation induced significant MEST difference (P<0.0001) was detected between KO and WT mice and was supported also by histopathology. A significant increase of CD4+ CD25+ activated T-cells (P<0.01) and elevated serum IgE levels (P<0.05) in KO mice indicated more the development of FITC sensibilization than an irritative reaction. P. acnes induced intracutaneous inflammation showed no difference (P=0.2254) between the reactivity of WT and KO immune system. As in vivo tracer, FITC penetration from skin surface followed by two-photon microscopy demonstrated a more invasive percutaneous penetration in KO mice. The clinically uninvolved skin in TGM3/KO mice showed impaired barrier function and higher susceptibility to FITC sensitization indicating that TGM3 has a significant contribution to the functionally intact cutaneous barrier.Journal of Investigative Dermatology accepted article preview online, 24 July 2013. doi:10.1038/jid.2013.307

Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3 regulatory T cells

Pasztoi M, Pezoldt J, Beckstette M, et al. Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3 regulatory T cells. European Journal of Immunology. 2017;47(12):2142-2152.Intestinal regulatory T cells (Tregs) are fundamental in peripheral tolerance toward commensals and food-borne antigens. Accordingly, gut-draining mesenteric lymph nodes (mLNs) represent a site of efficient peripheral de novo Treg induction when compared to skin-draining peripheral LNs (pLNs), and we had recently shown that LN stromal cells substantially contribute to this process. Here, we aimed to unravel the underlying molecular mechanisms and generated immortalized fibroblastic reticular cell lines (iFRCs) from mLNs and pLNs, allowing unlimited investigation of this rare stromal cell subset. In line with our previous findings, mLN-iFRCs showed a higher Treg-inducing capacity when compared to pLN-iFRCs. RNA-seq analysis focusing on secreted molecules revealed a more tolerogenic phenotype of mLN- as compared to pLN-iFRCs. Remarkably, mLN-iFRCs produced substantial numbers of microvesicles (MVs) that carried elevated levels of TGF-β when compared to pLN-iFRC-derived MVs, and these novel players of intercellular communication were shown to be responsible for the tolerogenic properties of mLN-iFRCs. Thus, stromal cells originating from mLNs contribute to peripheral tolerance by fostering de novo Treg induction using TGF-β-carrying MVs. This finding provides novel insights into the subcellular/molecular mechanisms of de novo Treg induction and might serve as promising tool for future therapeutic applications to treat inflammatory disorders

Yersinia Pseudotuberculosis Modulates Regulatory T Cell Stability via Injection of Yersinia Outer Proteins in a Type III Secretion System-Dependent Manner.

Adaptive immunity is essentially required to control acute infection with enteropathogeni