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In response to viral infection, CD8 + T cells undergo expansion and differentiate into distinct classes of effector cells. After clearance of the virus, a small population of long-lived memory cells persists. Comprehensive studies have defined the protein-coding transcriptional changes associated with this process. Here we expand on this prior work by performing RNA-sequencing to identify changes in long noncoding RNA (lncRNA) expression in human and mouse CD8 + T cells responding to viral infection. We identify hundreds of unannotated lncRNAs and show that expression profiles of both known and novel lncRNAs are sufficient to define naive, effector, and memory CD8 + T cell subsets, implying that they may be involved in fate decisions during antigen-driven differentiation. Additionally, in comparing mouse and human lncRNA expression, we find that lncRNAs with conserved sequence undergo similar changes in expression in the two species, suggesting an evolutionarily conserved role for lncRNAs during CD8 + T cell differentiation. Long noncoding RNA (lncRNA) genes do not encode protein products yet are emerging as key regulators of cellular processes such as transcription and translation. Here, by examining lncRNA profiles from human and mouse CD8 T cells, the authors show that stages of CD8 + T cell differentiation are defined by expression of lncRNA genes.

Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models were first fit to the frequency of YFV-specific memory CD8 T cells and deuterium enrichment in those cells 42 days to 1 year post-vaccination. A different dataset, on the loss of YFV-specific CD8 T cells over three decades, was used to assess out of sample predictions of our models. The commonly used exponential and bi-exponential decline models performed relatively poorly. Models with the cell loss following a power law (exactly or approximately) were most predictive. Notably, using only the first year of data, these models accurately predicted T cell frequencies up to 30 years post-vaccination. Our analyses suggest that division rates of these cells drop and plateau at a low level (0.1% per day, ∼ double the estimated values for naive T cells) within one year following vaccination, whereas death rates continue to decline for much longer. Our results show that power laws can be predictive for T cell memory, a finding that may be useful for vaccine evaluation and epidemiological modeling. Moreover, since power laws asymptotically decline more slowly than any exponential decline, our results help explain the longevity of immune memory phenomenologically.

Inhibitors of glycogen synthase kinase 3 (GSK3) are being explored as therapy for chronic inflammatory diseases. We previously demonstrated that the GSK inhibitor lithium is beneficial in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. In this study we report that lithium suppresses EAE induced by encephalitogenic interferon-γ (IFN-γ)-producing T helper (Th1) cells but not by interleukin (IL)-17-producing T helper (Th17) cells. The therapeutic activity of lithium required functional IFN-γ-signaling, but not the receptor for type I IFN (IFNAR). Inhibitor/s of GSK3 attenuated IFN-γ dependent activation of the transcription factor STAT1 in naïve T cells as well as in encephalitogenic T cells and Th1 cells. The inhibition of STAT1 activation was associated with reduced IFN-γ production and decreased expansion of encephalitogenic Th1 cells. Furthermore, lithium treatment induced Il27 expression within the spinal cords of mice with EAE. In contrast, such treatment of Ifngr(-/-) mice did not induce Il27 and was associated with lack of therapeutic response. Our study reveals a novel mechanism for the efficacy of GSK3 targeting in EAE, through the IFN-γ-STAT1 axis that is independent IFNAR-STAT1 axis. Overall our findings set the framework for the use of GSK3 inhibitors as therapeutic agents in autoimmune neuroinflammation.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection 1 . Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1 + TCF1 + stem-like CD8 +  T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8 +  T cells that resemble highly functional effector CD8 +  T cells seen after an acute viral infection. The generation of these qualitatively superior CD8 + T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1 + TCF1 + stem-like CD8 + T cells, also referred to as precursors of exhausted CD8 + T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8 + T cells emerging from the stem-like CD8 + T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25–CD122–CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer 2 , 3 , and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies. PD-1 + TCF1 + stem-like CD8 + T cells—precursors of exhausted CD8 + T cells—are not fate-locked into the exhaustion program; their differentiation trajectory can be changed by IL-2 signals.

The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen. In vivo deuterium labelling reveals a quiescent population of long-lived human virus-specific memory CD8 T cells that maintain the epigenetic landscape of effector cells, which facilitates rapid responses to pathogen re-exposure. A pathogen to remember Memory cells protect against reinfection, or protect against infection after vaccination, but whether they are derived from naive or effector T cells is unknown. Rafi Ahmed and colleagues study the generation, maintenance and characteristics of long-lived memory CD8 T cells in humans after yellow fever vaccination and deuterium labelling. The study demonstrates that long-lived memory CD8 T cells are derived from cells that have divided extensively during the effector phase of the infection. Quiescent memory cells appear to revert to a naive phenotype but maintain an upregulated pattern of gene regulation that resembles effector T cells. In a second paper in this issue, Rafi Ahmed and colleagues examine changes in DNA methylation during effector and memory CD8 T cell differentiation, providing support for a model in which long-lived memory cells arise from a precursor of effector cells.

Inhibitors of glycogen synthase kinase 3 (GSK3) are being explored as therapy for chronic inflammatory diseases. We previously demonstrated that the GSK inhibitor lithium is beneficial in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. In this study we report that lithium suppresses EAE induced by encephalitogenic interferon-[gamma] (IFN-[gamma])-producing T helper (Th1) cells but not by interleukin (IL)-17-producing T helper (Th17) cells. The therapeutic activity of lithium required functional IFN-[gamma]-signaling, but not the receptor for type I IFN (IFNAR). Inhibitor/s of GSK3 attenuated IFN-[gamma] dependent activation of the transcription factor STAT1 in naïve T cells as well as in encephalitogenic T cells and Th1 cells. The inhibition of STAT1 activation was associated with reduced IFN-[gamma] production and decreased expansion of encephalitogenic Th1 cells. Furthermore, lithium treatment induced Il27 expression within the spinal cords of mice with EAE. In contrast, such treatment of Ifngr.sup.-/- mice did not induce Il27 and was associated with lack of therapeutic response. Our study reveals a novel mechanism for the efficacy of GSK3 targeting in EAE, through the IFN-[gamma]-STAT1 axis that is independent IFNAR-STAT1 axis. Overall our findings set the framework for the use of GSK3 inhibitors as therapeutic agents in autoimmune neuroinflammation.

This paper employs a simple stochastic model to investigate how transaction cost and strategic option considerations interact to influence a firm's evaluation of collaborative venturing as a market entry mode. After demonstrating how uncertainty about the market and about the potential partner can add to the value of a collaborative venture, the paper explicates a condition under which the option to acquire or sell out generates a positive economic value for both of the partners. The interaction of transaction cost and strategic option considerations is then examined, and a number of testable hypotheses are proposed based on the theoretical analyses of the paper.

CD5 is expressed on T and B1a cells and is an important regulator of cell survival and activation. Engagement of CD5 promotes cell survival through the activation of the serine threonine kinase CK2. Mice with genetic abrogation of CD5 binding to CK2 (CD5ΔCK2bd) exhibited reduced severity of experimental autoimmune encephalomyelitis that was associated with increased activation induced cell death. In addition to inhibiting cell death, CD5 activation of CK2 significantly enhances Th17 differentiation. Loss of CD5-CK2 signaling reduces the generation of Th17 cells despite an unexpected increase in pSTAT3 levels. The mechanisms of CD5's enhancement of Th17 differentiation have not been previously described. I have determined that CD5-CK2 signaling enhances Th17 differentiation through activation of the AKT signaling pathway. CD5 activation of AKT increases nuclear levels of RORγt and further augments Th17 differentiation by inhibiting GSK3. Pharmacological inhibition of GSK3 significantly enhances Th17 differentiation within the first three days of stimulation. Furthermore, GSK3 is necessary for optimal IFN-γR signaling in T cells and inhibition of GSK3 by CD5 dampens IFN-γ inhibition of Th17 differentiation. I sought to determine if CD5-CK2 signaling affected other cytokine receptors. Because, the IL-6 receptor requires CK2 activity for STAT activation we hypothesized that CD5 could enhance IL-6 signaling. Surprisingly, CD5 does not alter IL-6R signaling, but CD5 was found to be a potent enhancer of IL-10R signaling. I determined that the IL-10R also requires active CK2 for STAT3 activation. CD5-CK2 signaling augments IL-10 inhibition of IL-2 secretion and increases expression of SOCS3. These results greatly broaden our understanding of the function of CD5. In addition to cell survival, CD5 enhances Th17 differentiation by enhancing nuclear translocation of RORγt and by inhibiting IFN-γR signaling. The IL-10R signaling is also enhanced by CD5 activation of CK2.

The taboos surrounding suicide are especially hard to penetrate when the suicide is that of a child. Concerned with presenting a clear picture, the authors discuss the difficulties in recognizing childhood suicide, presuicidal conditions and behaviors, and methods for prevention.

By coupling synoptic data from a basin-wide assessment of streamwater chemistry with network-based geostatistical analysis, we show that spatial processes differentially affect biogeochemical condition and pattern across a headwater stream network. We analyzed a high-resolution dataset consisting of 664 water samples collected every 100 m throughout 32 tributaries in an entire fifth-order stream network. These samples were analyzed for an exhaustive suite of chemical constituents. The fine grain and broad extent of this study design allowed us to quantify spatial patterns over a range of scales by using empirical semivariograms that explicitly incorporated network topology. Here, we show that spatial structure, as determined by the characteristic shape of the semivariograms, differed both among chemical constituents and by spatial relationship (flow-connected, flow-unconnected, or Euclidean). Spatial structure was apparent at either a single scale or at multiple nested scales, suggesting separate processes operating simultaneously within the stream network and surrounding terrestrial landscape. Expected patterns of spatial dependence for flow-connected relationships (e.g., increasing homogeneity with downstream distance) occurred for some chemical constituents (e.g., dissolved organic carbon, sulfate, and aluminum) but not for others (e.g., nitrate, sodium). By comparing semivariograms for the different chemical constituents and spatial relationships, we were able to separate effects on streamwater chemistry of (i) fine-scale versus broad-scale processes and (ii) in-stream processes versus landscape controls. These findings provide insight on the hierarchical scaling of local, longitudinal, and landscape processes that drive biogeochemical patterns in stream networks.