Activated iNKT Cells Promote Memory CD8+ T Cell Differentiation during Viral Infection

α-galactosylceramide (α-GalCer) is the prototypical lipid ligand for invariant NKT cells. Recent studies have proposed that α-GalCer is an effective adjuvant in vaccination against a range of immune challenges, however its mechanism of action has not been completely elucidated. A variety of delivery methods have been examined including pulsing dendritic cells with α-GalCer to optimize the potential of α-GalCer. These methods are currently being used in a variety of clinical trials in patients with advanced cancer but cannot be used in the context of vaccine development against pathogens due to their complexity. Using a simple delivery method, we evaluated α-GalCer adjuvant properties, using the mouse model for cytomegalovirus (MCMV). We measured several key parameters of the immune response to MCMV, including inflammation, effector, and central memory CD8+ T cell responses. We found that α-GalCer injection at the time of the infection decreases viral titers, alters the kinetics of the inflammatory response, and promotes both increased frequencies and numbers of virus-specific memory CD8+ T cells. Overall, our data suggest that iNKT cell activation by α-GalCer promotes the development of long-term protective immunity through increased fitness of central memory CD8+ T cells, as a consequence of reduced inflammation

Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude.

TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF

Regulation of T Cell Trafficking by Enzymatic Synthesis of O-Glycans

Selectins constitute a family of oligosaccharide binding proteins that play critical roles in regulating the trafficking of leukocytes. In T cells, L-selectin (CD62L) controls the capacity for naive and memory T cells to actively survey peripheral lymph nodes, whereas P- and E-selectin capture activated T cells on inflamed vascular endothelium to initiate extravasation into non-lymphoid tissues. The capacity for T cells to interact with all of these selectins is dependent on the enzymatic synthesis of complex O-glycans, and thus, this protein modification plays an indispensable role in regulating the distribution and homing of both naive and previously activated T cells in vivo. In contrast to neutrophils, O-glycan synthesis is highly dynamic in T cell populations and is largely controlled by extracellular stimuli such as antigen recognition or signaling though cytokine receptors. Herein, we review the basic principles of enzymatic synthesis of complex O-glycans, discuss tools and reagents for studying this type of protein modification and highlight our current understanding of how O-glycan synthesis is regulated and subsequently impacts the trafficking potential of diverse T cell populations

Central memory CD8+ T cells become CD69+ tissue-residents during viral skin infection independent of CD62L-mediated lymph node surveillance.

Memory CD8+ T cells in the circulation rapidly infiltrate non-lymphoid tissues following infection and provide protective immunity in an antigen-specific manner. However, the subsequent fate of memory CD8+ T cells after entering non-lymphoid tissues such as the skin during a secondary infection is largely unknown. Furthermore, because expression of CD62L is often used to identify the central memory (TCM) CD8+ T cell subset, uncoupling the physical requirement for CD62L-mediated lymph node homing versus other functional attributes of TCM CD8+ T cells remains unresolved. Here, we show that in contrast to naïve CD8+ T cells, memory CD8+ T cells traffic into the skin independent of CD62L-mediated lymph node re-activation and provide robust protective immunity against Vaccinia virus (VacV) infection. TCM, but not effector memory (TEM), CD8+ T cells differentiated into functional CD69+/CD103- tissue residents following viral clearance, which was also dependent on local recognition of antigen in the skin microenvironment. Finally, we found that memory CD8+ T cells expressed granzyme B after trafficking into the skin and utilized cytolysis to provide protective immunity against VacV infection. Collectively, these findings demonstrate that TCM CD8+ T cells become cytolytic following rapid infiltration of the skin to protect against viral infection and subsequently differentiate into functional CD69+ tissue-residents

T helper 1 effector memory CD4+ T cells protect the skin from poxvirus infection

Summary: Poxvirus infections of the skin are a recent emerging public health concern, yet the mechanisms that mediate protective immunity against these viral infections remain largely unknown. Here, we show that T helper 1 (Th1) memory CD4+ T cells are necessary and sufficient to provide complete and broad protection against poxvirus skin infections, whereas memory CD8+ T cells are dispensable. Core 2 O-glycan-synthesizing Th1 effector memory CD4+ T cells rapidly infiltrate the poxvirus-infected skin microenvironment and produce interferon γ (IFNγ) in an antigen-dependent manner, causing global changes in gene expression to promote anti-viral immunity. Keratinocytes express IFN-stimulated genes, upregulate both major histocompatibility complex (MHC) class I and MHC class II antigen presentation in an IFNγ-dependent manner, and require IFNγ receptor (IFNγR) signaling and MHC class II expression for memory CD4+ T cells to protect the skin from poxvirus infection. Thus, Th1 effector memory CD4+ T cells exhibit potent anti-viral activity within the skin, and keratinocytes are the key targets of IFNγ necessary for preventing poxvirus infection of the epidermis

Transcriptome Changes in the Alzheimer's Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes

We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer's disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD