Hepatic natural killer (NK) cells mediate antigen (Ag)-specific contact hypersensitivity (CHS) in T-cell and B-cell deficient mice. We now report that hepatic, but not splenic or naïve NK cells also develop specific memory to vaccines containing Ags from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus-1 (HIV). Adoptive transfer of virus-sensitized NK cells to naïve recipients enhanced the animals' survival upon lethal challenge with the sensitizing virus, but not a different virus. NK cell memory to haptens and viruses depended upon CXCR6, a chemokine receptor on hepatic NK cells that was required for memory NK cell persistence but not for Ag recognition. Hence, hepatic NK-cells can develop adaptive immunity to structurally diverse Ags, an activity that requires NK-cell-expressed CXCR6.

After homing to lymph nodes, CD8 + T cells are primed by dendritic cells (DCs) in three phases. During phase one, T cells undergo brief serial contacts with DCs for several hours, whereas phase two is characterized by stable T cell-DC interactions. We show here that the duration of phase one and T cell activation kinetics correlated inversely with the number of complexes of cognate peptide and major histocompatibility complex (pMHC) per DC and with the density of antigen-presenting DCs per lymph node. Very few pMHC complexes were necessary for the induction of full-fledged T cell activation and effector differentiation. However, neither T cell activation nor transition to phase two occurred below a threshold antigen dose determined in part by pMHC stability. Thus, phase one permits T cells to make integrated 'measurements' of antigen dose that determine subsequent T cell participation in immune responses.The naive T cell population expresses a broad array of unique T cell antigen receptors (TCRs), each with a discrete affinity for a given complex of cognate peptide and major histocompatibility complex (pMHC). Naive T cells constantly survey and sample antigenpresenting cells (APCs) in secondary lymphoid tissues in search of rare cognate pMHC complexes 1 . Due to the diversity of the TCR repertoire, only one in 1 × 10 5 to 1 × 10 6 T cells expresses a TCR with sufficient affinity for any given antigen to transmit an activating Correspondence should be addressed to U. H.v.A. (E-mail: uva@cbr.med.harvard.edu). Note: Supplementary information is available on the Nature Immunology website. AUTHOR CONTRIBUTIONSS.E.H. designed the study, did and analyzed experiments, and wrote the manuscript; U.H.v.A designed the study and wrote the manuscript; T.R.M., I.B.M., A.P., M.P.F., B.S. and T.J. did experiments; B.L. and H.C.W. provided reagents; and M.N.A., H.Z. and A.K.C. modeled the experimental data. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/natureimmunology/.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript stimulus 2,3 . Activation of naive T cells also requires costimulatory and cytokine signals 4,5 , which are typically provided by mature dendritic cells (DCs) in secondary lymphoid tissues 6 . As they 'hunt' for their cognate antigen, naive T cells recirculate between the blood and lymph nodes and spend less than 1 d in any given secondary lymphoid tissue 1,7 . When T cells encounter antigen in the proper context, they become activated and upregulate the activation marker CD69, which causes their retention in lymph nodes 8 . The trapped cells proliferate and acquire effector functions. Effector cells egress from lymph nodes and travel to peripheral tissues to seek out cells presenting cognate antigen 9 .Although this chain of events is well establ...

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Summary T cells are activated by antigen (Ag) bearing dendritic cells (DCs) in lymph nodes in 3 phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8+ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, while higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation, but yielded different transcriptome signatures at 12h and 24h. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics.

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This paper describes a neurostimulation IC for use in advanced closed-loop neurostimulation applications, such as deep brain stimulation (DBS) for treatment and research of neurological disorders including Parkinson's disease. This system senses and filters neural activity with eight pre-amplifiers, a 200 kS/s 8-bit log ADC and digital filters and incorporates 64 programmable current-stimulation channels. The entire device, implemented in 0.18 m CMOS, occupies 2.7 mm 2 and consumes 89 W in normal operation mode and 271 W in configuration mode from a 1.8 V supply.

We surveyed Delta1-pyrroline 5-carboxylate dehydrogenase genes from four patients with hyperprolinemia type II using RT-PCR amplification, genomic PCR amplification and direct sequencing. We found four mutant alleles, two with frameshift mutations [A7fs(-1) and G521fs(+1)] and two with missense mutations (S352L and P16L). To test the functional consequences of three of these, we expressed them in a P5CDh-deficient strain of Saccharomyces cerevisiae . In contrast to wild-type human P5CDh, yeast expressing S352L and G521fs(+1) failed to grow on proline and had no detectable P5CDh activity. The P16L allele, however, produced fully functional P5CDh and subsequent analysis suggests that it is polymorphic in the relevant (Spanish) population. Interestingly, the G521fs(+1) allele segregates in the large Irish Traveller pedigree used to define the HPII phenotype. To our knowledge, this is the first description of the molecular basis for this inborn error.