Phenotype and function of neonatal DC.

Newborns face complex physical and immunological changes before and after birth. Although the uterus is a sterile environment for the fetus, it also contains non-self material from the mother. Birth involves the transition from the sterile intra-uterine environment to an environment rich in microbes and requires rapid induction of appropriate responses to control these microbes. In this review we focus on the similarities and differences of human and murine neonatal DC and their reaction to various stimuli. A better understanding of the newborn immune system--in particular, the DC-T-cell interaction--will be beneficial for the development of improved strategies to prevent or treat infections in this vulnerable population and prepare the immune system to cope with allergens and tumors later in life.

No evidence for association between the interferon regulatory factor 1 (IRF1) gene and clinical tuberculosis.

Interferon regulatory factor 1 is a transcription factor involved in initiating a vigorous Th1 response during Mycobacterium tuberculosis infection. Therefore, we considered it as a possible candidate gene for certain polymorphisms to confer susceptibility to develop clinical tuberculosis. However, all polymorphisms with minor allele frequencies higher than 5% and haplotype frequencies in two Southeast Asian populations (Indonesian and Vietnamese) turned out not to be associated with pulmonary tuberculosis.

The contribution of transcription factor IRF1 to the interferon-gamma-interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells.

Interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) drive T helper type 1 (T(H)1) differentiation, but the mechanisms underlying the regulation of the complicated gene networks involved in this differentiation are not fully understood. Here we show that the IFN-gamma-induced transcription factor IRF1 was essential in T(H)1 differentiation by acting on Il12rb1, the gene encoding the IL-12 receptor beta1 subunit (IL-12Rbeta1). IRF1 directly interacted with and activated the Il12rb1 promoter in CD4+ T cells. Notably, the IRF1-dependent induction of IL-12Rbeta1 was essential for IFN-gamma-IL-12 signaling but was dispensable for IL-23-IL-17 signaling. Because both IL-12 and IL-23 bind to and transmit signals through IL-12Rbeta1, our data suggest that distinct thresholds of IL-12Rbeta1 expression are required for T(H)1 versus T(H)-17 differentiation.

The long-term but not the short-term antiviral effect of IFN-alpha depends on Flt3 ligand and pDC.

The cooperation between IFN-alpha/beta and FL, the ligand of Fms-like tyrosine kinase 3 (Flt3), plays an important role in the defense against herpes simplex virus type 1 (HSV-1) in neonates. Treatment of neonatal mice with recombinant IFN-alpha has a short-term, FL-independent and a long-term, FL-dependent protective effect against HSV-1. In mice lacking FL, neonatal resistance against HSV-1 is very low and DC numbers in the spleen are reduced. The treatment of these mice with rIFN-alpha at day 6 resulted in an increased resistance against infection with HSV-1 at day 7. In C57BL/6 mice, treatment with rIFN-alpha at birth induced both FL and plasmacytoid DC (pDC), resulting in enhanced resistance against HSV-1 at day 7. In contrast, in mice lacking FL, IFN-alpha treatment at birth did not influence the splenic cell composition and had no effect on viral protection. The transfer of pDC to mice lacking FL enhanced viral resistance. Therefore, the induction and function of pDC, normally controlled by IFN-alpha/beta and FL, are decisive for viral resistance in neonatal mice.

Treatment of neonatal mice with Flt3 ligand leads to changes in dendritic cell subpopulations associated with enhanced IL-12 and IFN-alpha production.

Treatment with the hematopoietic growth factor Flt3 ligand (FL) increases DC numbers in neonatal mice and enhances their resistance against intracellular pathogens. Flow cytometric analysis showed the presence of conventional DC (cDC) and plasmacytoid pre-DC (pDC) in neonatal spleens from untreated and FL-treated mice. CD8alpha and MHC class II expression on cDC and pDC was higher on DC from FL-treated mice than on DC from control littermates. After FL treatment, two additional subpopulations of DC-lineage cells were found that were able to produce IL-12 and IFN-alpha. The IL-12 production of cDC from FL-treated animals was more than 50-fold increased and their ability to stimulate T cell proliferation was also increased. We conclude that the enhanced resistance against intracellular pathogens was due to increased numbers of DC-lineage cells and their increased ability to produce the essential cytokines.

Dendritic cells from mice neonatally vaccinated with modified vaccinia virus Ankara transfer resistance against herpes simplex virus type I to naive one-week-old mice.

Modified vaccinia Ankara (MVA) is an attenuated virus. MVA induces the production of IFN and Flt3-L (FL), which results in the expansion of dendritic cells (DC) and enhanced resistance against viral infections. We report on the interplay among IFN, FL, and DC in the resistance against heterologous virus after injection of neonatal mice with MVA. The induction of serum FL was tested on day 2, and the expansion of DC was tested 1 wk after treatment with MVA. At this time point the resistance against infection with heterologous virus was also determined. After MVA treatment, serum FL was enhanced, and DC, including plasmacytoid cells in spleen, were increased in number. Mice that lacked functional IFN type I and II systems failed to increase both the concentration of FL and the number of DC. Treatment with MVA enhanced resistance against HSV-1 in wild-type animals 100-fold, but animals without a functional IFN system were not protected. Transfer of CD11c(+) cells from MVA-treated mice into naive animals protected against lethal infection with HSV-1. Thus, although the increased resistance could be largely attributed to the increase in activation of IFN-producing plasmacytoid cells, this, in turn, depends on a complex interplay between the DC and T cell systems involving both FL and IFNs.

Interplay between alpha/beta and gamma interferons with B, T, and natural killer cells in the defense against herpes simplex virus type 1.

The essential components of the immune system that control primary and chronic infection with herpes simplex virus type 1 (HSV-1) in mice were investigated. Infection within the first few days can be controlled by alpha/beta interferon (IFN-alpha/beta) alone without significant contribution of B, T, or NK cells. IFN-alpha/beta and IFN-gamma cooperate in the elimination of virus in the absence of these lymphocytes. In contrast, B, T, or NK cells appear to be required to control persistent infection with HSV-1. These results suggest that distinct and essential immune elements are recruited in a time-dependent fashion to control acute and persistent HSV-1 infection.

Flt3 ligand-treated neonatal mice have increased innate immunity against intracellular pathogens and efficiently control virus infections.

Flt-3 ligand (FL), a hematopoetic growth factor, increases the number of dendritic cells (DCs), B cells, and natural killer cells in adult mice but the effect in neonates was unknown. We show that FL treatment of newborn mice induced a >100-fold increase in the innate resistance against infection with herpes simplex virus type 1 and Listeria monocytogenes. This resistance required interferon (IFN)-alpha/beta for viral and interleukin (IL)-12 for bacterial infections. Long-term survival after viral but not bacterial infection was increased approximately 100-fold by FL treatment. After treatment, CD11c(+)/major histocompatibility complex type II(+) and CD11c(+)/B220(+) DC lineage cells were the only cell populations increased in the spleen, liver, peritoneum, and skin. DC induction was independent of IFNs, IL-2, -4, -7, -9, -15, and mature T and B cells. The data suggest that FL increases the number of DCs in neonates and possibly in other immune-compromised individuals, which in turn improves IFN-alpha/beta- and IL-12-associated immune responses.