The fetus and newborn face a complex set of immunological demands, including protection against infection, avoidance of harmful inflammatory immune responses that can lead to pre-term delivery, and balancing the transition from a sterile intra-uterine environment to a world that is rich in foreign antigens. These demands shape a distinct neonatal innate immune system that is biased against the production of pro-inflammatory cytokines. This bias renders newborns at risk of infection and impairs responses to many vaccines. This Review describes innate immunity in newborns and discusses how this knowledge might be used to prevent and treat infection in this vulnerable population.

NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an ''alternative self'' mechanism for MHC class I inhibition.inhibitory receptors ͉ natural killers I n contrast to T cells, that possess a single dominant antigen receptor (1), NK cells rely on a vast combinatorial array of receptors to initiate effector functions (2). Both activating and inhibitory receptors expressed on NK cells regulate their activity when interacting with tumors, virus infected cells and bacteria, as well as normal self-cells (2). MHC class I-expressing cells are protected from NK-mediated lysis due to the recognition of various MHC class I proteins by the inhibitory receptors KIR, LIR and CD94-NKG2A (3). Other NK inhibitory receptors which do not interact with MHC class I also exist, such as CEACAM1 and IRp60 (4-8). The significance, however, of these non-MHC class I inhibitory receptors in normal conditions is still unclear. All of the inhibitory receptors share a common immune receptor tyrosinebased inhibitory motif (ITIM) in their cytoplasmic regions, which delivers the inhibitory signal (3).The NK cell-mediated killing is extracted by specific receptors, among which are the natural cytotoxicity receptors (NCRs), which include the NKp30 that interacts with pp65 of human cytomegalovirus (CMV), BAT3 and the recently identified B7-family member B7-H6 (9-11), and the NKp46/NKp44 receptors, which interact with various viral hemagglutinins (12, 13). The NKG2D receptor interacts with MICA, MICB and ULBP 1-5 (14) and NKp80 interacts with AICL (15). In addition, two other receptors, DNAM-1 and CD96, enhance NK cytotoxicity (16,17). Both DNAM-1 and CD96 recognize PVR (CD155), whereas DNAM-1 also recognizes PVRL2 (CD112) (16,17). It was recently shown that a new receptor, named TIGIT, for T cell Ig and ITIM domain, interacts with PVR and its related proteins and that TIGIT inhibits T cell activity indirectly through the manipulation of DC activity (18). Here, we show that TIGIT, through its ITIM, can directly inhibit NK cytotoxicity. ResultsTIGIT Inhibits YTS Killing Through Its ITIM Motif. While searching for new CD28 family-like receptors, based on bioinformatics analysis, we observed that a protein named VSIG9 or VSTM3 in the databases expresses an ITIM motif. We continued to work on this protein and found that it interacts with PVR (CD155) but not with any other NK ligands tested (supporting information (...

Summary Given the "inborn" nature of the innate immune system, it is surprising to find that innate immune function does in fact change with age. Similar patterns of distinct Toll-like receptor (TLR)-mediated immune responses come to light when one contrasts innate immune development at the beginning of life with that toward the end of life. Importantly, these developmental patterns of innate cytokine responses correlate with clinical patterns of susceptibility to disease: A heightened risk of suffering from excessive inflammation is often detected in prematurely born infants, disappears over the first few months of life, and reappears toward the end of life. In addition, risk periods for particular infections in early life reemerge in older adults. The near-mirror-image patterns that emerge in contrasts of early versus late innate immune ontogeny emphasize changes in host-environment interactions as the underlying molecular and teleologic drivers.