CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection.

Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4(+) T cells are important for the formation of functional lung-resident CD8(+) T cells after influenza virus infection. In the absence of CD4(+) T cells, CD8(+) T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8(+) T cells to the lung airways upon heterosubtypic challenge. CD4(+) T cell-derived interferon-γ was necessary for generating lung-resident CD103(+) CD8(+) Trm cells. Furthermore, expression of the transcription factor T-bet was increased in "unhelped" lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4(+) T cell help. Thus, CD4(+) T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103(+) CD8(+) Trm cells in the lung airways following respiratory infection.

Review on Monitoring, Operation and Maintenance of Smart Offshore Wind Farms.

In recent years, with the development of wind energy, the number and scale of wind farms have been developing rapidly. Since offshore wind farms have the advantages of stable wind speed, being clean, renewable, non-polluting, and the non-occupation of cultivated land, they have gradually become a new trend in the wind power industry all over the world. The operation and maintenance of offshore wind power has been developing in the direction of digitization and intelligence. It is of great significance to carry out research on the monitoring, operation, and maintenance of offshore wind farms, which will be of benefit for the reduction of the operation and maintenance costs, the improvement of the power generation efficiency, improvement of the stability of offshore wind farm systems, and the building of smart offshore wind farms. This paper will mainly summarize the monitoring, operation, and maintenance of offshore wind farms, with particular focus on the following points: monitoring of "offshore wind power engineering and biological and environment", the monitoring of power equipment, and the operation and maintenance of smart offshore wind farms. Finally, the future research challenges in relation to the monitoring, operation, and maintenance of smart offshore wind farms are proposed, and the future research directions in this field are explored, especially in marine environment monitoring, weather and climate prediction, intelligent monitoring of power equipment, and digital platforms.

Uncoupling glucose sensing from GAL metabolism for heterologous lactose fermentation in Saccharomyces cerevisiae.

OBJECTIVES: Development of a system for direct lactose to ethanol fermentation provides a market for the massive amounts of underutilized whey permeate made by the dairy industry. For this system, glucose and galactose metabolism were uncoupled in Saccharomyces cerevisiae by deleting two negative regulatory genes, GAL80 and MIG1, and introducing the essential lactose hydrolase LAC4 and lactose transporter LAC12, from the native but inefficient lactose fermenting yeast Kluyveromyces marxianus. RESULTS: Previously, integration of the LAC4 and LAC12 genes into the MIG1 and NTH1 loci was achieved to construct strain AY-51024M. Low rates of lactose conversion led us to generate the Δmig1Δgal80 diploid mutant strain AY-GM from AY-5, which exhibited loss of diauxic growth and glucose repression, subsequently taking up galactose for consumption at a significantly higher rate and yielding higher ethanol concentrations than strain AY-51024M. Similarly, in cheese whey permeate powder solution (CWPS) during three, repeated, batch processes in a 5L bioreactor containing either 100 g/L or 150 g/L lactose, the lactose uptake and ethanol productivity rates were both significantly greater than that of AY-51024M, while the overall fermentation times were considerably lower. CONCLUSIONS: Using the Cre-loxp system for deletion of the MIG1 and GAL80 genes to relieve glucose repression, and LAC4 and LAC12 overexpression to increase lactose uptake and conversion provides an efficient basis for yeast fermentation of whey permeate by-product into ethanol.

Solution-processed antireflective coating for back-contact perovskite solar cells.

Back-contact architectures for perovskite solar cells eliminate parasitic-absorption losses caused by the electrode and charge collection layers but increase surface reflection due to the high refractive index mismatch at the air/perovskite interface. To mitigate this, a ∼85 nm thick layer of poly(methyl methacrylate) (PMMA), with a refractive index between those of air and perovskite, has been applied as an antireflective coating. Transfer matrix modelling is used to determine the ideal PMMA layer thickness, with UV-Vis spectroscopy measurements used to confirm the increase in absorption that arises through the application of the antireflective coating. The deposition of a thin film of PMMA via spin coating onto a solar cell results in a 20-30% relative increase in short circuit current density and stable power output density.

Epimedin C Protects H2O2-Induced Peroxidation Injury by Enhancing the Function of Endothelial Progenitor HUVEC Populations.

Endothelial cell injury and apoptosis induced by oxidative stress serve important roles in many vascular diseases. The repair of endothelial cell vascular injury relies on the function of local endothelial progenitor cells (EPCs). Our previous study indicated that epimedin C, a major flavonoid derived from Herba epimedii (yin yang huo), could promote vascularization by inducing endothelial-like differentiation of mesenchymal stem cells C3H/10T1/2 both in vivo and in vitro. In view of the significant cardiovascular protective effects of Herba epimedii, we detected a protective effect of epimedin C on hydrogen peroxide (H2O2)-induced peroxidation injury in human umbilical vein endothelial cells (HUVECs) and the role of EPC in this process. The results show that epimedin C increased the expression of the stem cell marker, CD34 and PROM1, and subsequently enhanced the expression and function of vascular endothelial growth factor and matrix metalloproteinase (MMP)-2 in local vascular endothelial cells. In conclusion, epimedin C protects H2O2-induced peroxidation injury by enhancing the function of endothelial progenitor HUVEC populations.

Smad4 promotes differentiation of effector and circulating memory CD8 T cells but is dispensable for tissue-resident memory CD8 T cells.

Tissue-resident memory CD8 T cells are a unique subset of virus-specific CTLs that bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CD8 T cells circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CD8 T cell populations in remote parts of the body. Both populations of virus-specific memory CD8 T cells participate in immunity to influenza virus infection; however, the signaling pathways that instruct developing memory CD8 T cells to distribute to specific tissues are poorly defined. We show that TGF-ß promotes the development of pulmonary tissue-resident memory T cells via a signaling pathway that does not require the downstream signaling intermediate Sma- and Mad-related protein (Smad)4. In contrast, circulating memory CD8 T cells have no requirement for TGF-ß but show signs of arrested development in the absence of Smad4, including aberrant CD103 expression. These signaling pathways alter the distribution of virus-specific CTLs in the lungs but do not prevent robust cytokine responses. Our data show that Smad4 is required for normal differentiation of multiple subsets of virus-specific CD8 T cells. In normal circumstances, Smad4 may be activated via a pathway that bypasses the TGF-ß receptor. Improved understanding of these signaling pathways could be used to augment vaccine-induced immunity.

Room temperature synthesis of covalent-organic framework films through vapor-assisted conversion.

We describe the facile synthesis of several two-dimensional covalent-organic frameworks (2D COFs) as films by vapor-assisted conversion at room temperature. High-quality films of benzodithiophene-containing BDT-COF and COF-5 with tunable thickness were synthesized under different conditions on various substrates. BDT-COF films of several micrometer thickness exhibit mesoporosity as well as textural porosity, whereas thinner BDT-COF films materialize as a cohesive dense layer. In addition, we studied the formation of COF-5 films with different solvent mixture compositions serving as vapor source. Room temperature vapor-assisted conversion is an excellent method to form COF films of fragile precursors and on sensitive substrates.

LGI1 is involved in the development of mouse brain.

Mutations in leucine-rich glioma inactivated 1 (LGI1) are linked to human autosomal dominant lateral temporal lobe epilepsy. It has been shown that LGI1 prevents the inactivation of voltage-gated potassium channels, mediates postnatal maturation of glutamatergic synapses, and regulates excitatory neurotransmission. However, other functions of LGI1 in the central nervous system have not been elucidated. We found that LGI1 is involved in the development of the cerebellum and cortex. The thickness of external granule layer was reduced, and foliation was affected in the cerebellum of LGI1 knockout mice. Double staining with Pax6 and BrdU showed a significant inhibition of proliferation of granule cell precursors of knockout embryos. The differentiation of radial glia cells was also suppressed in knockout mice, as shown by increased radial glial cells and decreased Bergmann glias in the areas of the cerebellum and cortex. Thus, our data demonstrate that LGI1 may be an essential player in the development of the brain.

The novel imaging methods in diagnosis and assessment of cerebrovascular diseases: an overview.

Cerebrovascular diseases, including ischemic strokes, hemorrhagic strokes, and vascular malformations, are major causes of morbidity and mortality worldwide. The advancements in neuroimaging techniques have revolutionized the field of cerebrovascular disease diagnosis and assessment. This comprehensive review aims to provide a detailed analysis of the novel imaging methods used in the diagnosis and assessment of cerebrovascular diseases. We discuss the applications of various imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and angiography, highlighting their strengths and limitations. Furthermore, we delve into the emerging imaging techniques, including perfusion imaging, diffusion tensor imaging (DTI), and molecular imaging, exploring their potential contributions to the field. Understanding these novel imaging methods is necessary for accurate diagnosis, effective treatment planning, and monitoring the progression of cerebrovascular diseases.

Impact of smoking cessation duration on lung cancer mortality: A systematic review and meta-analysis.

BACKGROUND: Smoking history is a heterogeneous situation for different populations, and numerous studies suggest that smoking cessation is conducive to reduce the mortality of lung cancer. However, no quantitative meta-analysis regarding smoking cessation duration based on different populations has demonstrated it clearly. METHODS: We systematically searched four electronic databases (PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Scoups) till February 2023. Eligible studies reported the association between lung cancer survival and duration of smoking cessation. Additionally, we stratified the study population according to whether they had lung cancer at the time they quit smoking. Studies were pooled with the random-effects model. RESULTS: Out of the 11,361 potential studies initially identified, we included 24 studies involving 969,560 individuals in our analysis. Lung cancer mortality varied across two groups: general quitters and peri-diagnosis quitters. For general quitters, those who had quit smoking for less than 10 years exhibited an RR of 0.64 (95% CI [0.55-0.76]), while those who quit for 10-20 years had an RR of 0.33 (0.25-0.43), over 20 years had an RR of 0.16 (0.11-0.24), and never-smokers had an RR at 0.11 (0.07-0.15). Among peri-diagnosis quitters, the 1-year Overall Survival (OS) showed an RR of 0.80 (0.67-0.96), the 2-year OS had an RR of 0.89 (0.80-0.98), the 3-year OS had an RR of 0.93 (0.84-1.03), and the 5-year OS had an RR of 0.85 (0.76-0.96). CONCLUSIONS: Earlier and longer smoking cessation is associated with reduced lung cancer mortality, no matter in which cessation stage for two different populations.

Early generation of a precursor CD8 T cell that can adapt to acute or chronic viral infection.

Virus specific PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells are essential for maintaining T cell responses during chronic infection and are also critical for PD-1 directed immunotherapy. In this study we have used the mouse model of chronic LCMV infection to examine when these virus specific stem-like CD8+ T cells are generated during the course of chronic infection and what is the role of antigen in maintaining the stem-like program. We found that these stem-like CD8+ T cells are generated early (day 5) during chronic infection and that antigen is essential for maintaining their stem-like program. This early generation of stem-like CD8+ T cells suggested that the fate commitment to this cell population was agnostic to the eventual outcome of infection and the immune system prepares a priori for a potential chronic infection. Indeed, we found that an identical virus specific stem-cell like CD8+ T cell population was also generated during acute LCMV infection but these cells were lost once the virus was cleared. To determine the fate of these early PD-1+TCF-1+TOX+ stem-like CD8+ T cells that are generated during both acute and chronic LCMV infection we set up two reciprocal adoptive transfer experiments. In the first experiment we transferred day 5 stem-like CD8+ T cells from chronically infected into acutely infected mice and examined their differentiation after viral clearance. We found that these early stem-like CD8+ T cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. In the second experiment, we transferred day 5 stem-like cells from acutely infected mice into chronically infected mice and found that these CD8+ T cells could function like resource cells after transfer into a chronic environment by generating effector CD8+ T cells in both lymphoid and non-lymphoid tissues while also maintaining the number of stem-like CD8+ T cells. These findings provide insight into the generation and maintenance of virus specific stem-like CD8+ T cells that play a critical role in chronic viral infection. In particular, our study highlights the early generation of stem-like CD8+ T cells and their ability to adapt to either an acute or chronic infection. These findings are of broad significance since these novel stem-like CD8+ T cells play an important role in not only viral infections but also in cancer and autoimmunity.

Retrograde cPLA2α/arachidonic acid/2-AG signaling is essential for cerebellar depolarization-induced suppression of excitation and long-term potentiation.

Cytosolic phospholipase A2 alpha (cPLA2α) responds to micromolar intracellular Ca(2+) and produces arachidonic acid, which regulates cellular homeostasis, neurotoxicity, and inflammation. Endocannabinoids are the derivates of arachidonic acid and widely distributed in the cerebellum. However, the role of cPLA2α/arachidonic acid pathway in cerebellar synaptic transmission and plasticity is unknown. We utilized cPLA2α knockout mice and slice whole-cell patch clamp to study the action of cPLA2α/arachidonic acid signaling on the depolarization-induced suppression of excitation (DSE) and long-term potentiation at parallel fiber-Purkinje cell synapses. Our data showed that DSE was significantly inhibited but rescued by arachidonic acid in cPLA2α knockout mice. The degradation enzyme of 2-arachidonoylglycerol (2-AG), monoacylglycerol lipase, blocked DSE, while another catabolism enzyme for N-arachidonoylethanolamine, fatty acid amide hydrolase, did not, suggesting that 2-AG is responsible for DSE in Purkinje cells. Co-application of paxilline reversed the blockade of DSE by internal K(+), indicating that large-conductance Ca(2+)-activated potassium channel is sufficient to inhibit cPLA2α/arachidonic acid-mediated DSE. On the other hand, we found that 1 Hz parallel fiber stimuli-triggered long-term potentiation (LTP) was deficient in cPLA2α knockout mice. LTP was also inhibited when AACOCF3, an inhibitor of cPLA2α, was given. Arachidonic acid was necessary for the LTP induction. Therefore, these data showed that cPLA2α/arachidonic acid/2-AG signaling pathway mediates DSE and LTP at parallel fiber-Purkinje cell synapse.

PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.

PD-1+TCF-1+ stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)-directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1- daughter cell alongside a self-renewing TCF-1+ sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1+TCF-1+ stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1-directed immunotherapy in humans.

Ionic Accumulation as a Diagnostic Tool in Perovskite Solar Cells: Characterizing Band Alignment with Rapid Voltage Pulses.

Despite record-breaking devices, interfaces in perovskite solar cells are still poorly understood, inhibiting further progress. Their mixed ionic-electronic nature results in compositional variations at the interfaces, depending on the history of externally applied biases. This makes it difficult to measure the band energy alignment of charge extraction layers accurately. As a result, the field often resorts to a trial-and-error process to optimize these interfaces. Current approaches are typically carried out in a vacuum and on incomplete cells, hence values may not reflect those found in working devices. To address this, a pulsed measurement technique characterizing the electrostatic potential energy drop across the perovskite layer in a functioning device is developed. This method reconstructs the current-voltage (JV) curve for a range of stabilization biases, holding the ion distribution "static" during subsequent rapid voltage pulses. Two different regimes are observed: at low biases, the reconstructed JV curve is "s-shaped", whereas, at high biases, typical diode-shaped curves are returned. Using drift-diffusion simulations, it is demonstrated that the intersection of the two regimes reflects the band offsets at the interfaces. This approach effectively allows measurements of interfacial energy level alignment in a complete device under illumination and without the need for expensive vacuum equipment.

The tomato SlIAA15 is involved in trichome formation and axillary shoot development.

The Aux/IAA genes encode a large family of short-lived proteins known to regulate auxin signalling in plants. Functional characterization of SlIAA15, a member of the tomato (Solanum lycopersicum) Aux/IAA family, shows that the encoded protein acts as a strong repressor of auxin-dependent transcription. The physiological significance of SlIAA15 was addressed by a reverse genetics approach, revealing that SlIAA15 plays multiple roles in plant developmental processes. The SlIAA15 down-regulated lines display lower trichome number, reduced apical dominance with associated modified pattern of axillary shoot development, increased lateral root formation and decreased fruit set. Moreover, the leaves of SlIAA15-inhibited plants are dark green and thick, with larger pavement cells, longer palisade cells and larger intercellular space of spongy mesophyll cells. The SlIAA15-suppressed plants exhibit a strong reduction in type I, V and VI trichome formation, suggesting that auxin-dependent transcriptional regulation is required for trichome initiation. Concomitant with reduced trichome formation, the expression of some R2R3 MYB genes, putatively involved in the control of trichome differentiation, is altered. These phenotypes uncover novel and specialized roles for Aux/IAAs in plant developmental processes, clearly indicating that members of the Aux/IAA gene family in tomato perform both overlapping and specific functions.

Activity of pemetrexed and high-dose gefitinib in an EGFR-mutated lung adenocarcinoma with brain and leptomeningeal metastasis after response to gefitinib.

About 20% to 40% of patients with non-small cell lung cancer (NSCLC) will develop brain metastases during the natural course of their disease. The prognosis for such patients is very poor with limited survival. In addition to the standard whole brain radiation therapy (WBRT), some studies have shown that chemotherapy drugs and/or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) can improve the outcome of these patients. Here, we report a stage IIIA patient who developed multiple brain metastases one year after operation. Oral gefitinib with concurrent WBRT were given as first-line therapy. Complete response and a 50-month progression-free survival (PFS) were obtained. Double dosage of gefitinib (500 mg per day) together with pemetrexed were given as the second-line therapy after the patient developed new brain lesions and leptomeningeal metastasis during the maintenance therapy of gefitinib. The PFS for the second-line therapy was six months. In total, the patient obtained an overall survival of 59 months since the first diagnosis of brain metastases. Mutational analysis showed a 15-nucleotide deletion and a missense mutation in exon 19 of the EGFR gene, and a missense mutation at codon 12 of the K-ras gene. These underlying genetic changes might partially explain the long-term survival of this patient after brain metastases when treated with concurrent or sequential therapies of EGFR-TKI, radiotherapy and chemotherapy.

Chestnuts in Fermented Rice Beverages Increase Metabolite Diversity and Antioxidant Activity While Reducing Cellular Oxidative Damage.

Foods containing chestnuts (Castanea mollissima Blume) are relatively uncommon, despite the high nutrient and starch contents and purported health benefits. In this study, we examine the flavor-related metabolites, volatile compounds, and amino acids in a traditional glutinous rice fermented beverage supplemented with chestnuts as a fermentation substrate for lactic acid bacteria (LAB). Changes in antioxidant activity towards free radicals and effects on cellular oxidative stress are compared between beverages with or without chestnuts. The fermented chestnut-rice beverage (FCRB) has higher sensory scores and a wider range of volatiles and flavor-related compounds (74 vs. 38 species compounds), but lower amino acid contents, than the traditional fermented glutinous rice beverage (TFRB). In free radical scavenging assays, the FCRB exhibits higher activity than the TFRB in vitro. Furthermore, while neither beverage induces cytotoxity in Caco-2 cells at concentrations up to 2 mg/mL, pretreatment with the FCRB results in lower rates of apoptosis and necrosis and higher overall viability in cells with H2O2-induced oxidative stress compared to pretreatment with the TFRB. The enhanced reactive oxygen species neutralization in vitro and protection against oxidative damage in cells, coupled with increased diversity of volatiles and flavor-related metabolites of LAB, support the addition of chestnuts to enhance flavor profile and antioxidant properties of fermented functional foods.

A Temperature-Dependent Model for Tritrophic Interactions Involving Tea Plants, Tea Green Leafhoppers and Natural Enemies.

The tea green leaf hopper, Empoasca onukii Matsuda, is a severe pest of tea plants. Volatile emissions from tea shoots infested by the tea green leafhopper may directly repel insect feeding or attract natural enemies. Many studies have been conducted on various aspects of the tritrophic relationship involving tea plants, tea green leafhoppers and natural enemies. However, mathematic models which could explain the dynamic mechanisms of this tritrophic interaction are still lacking. In the current work, we constructed a realistic and stochastic model with temperature-dependent features to characterize the tritrophic interactions in the tea agroecosystem. Model outputs showed that two leafhopper outbreaks occur in a year, with their features being consistent with field observations. Simulations showed that daily average effective accumulated temperature (EAT) might be an important metric for outbreak prediction. We also showed that application of slow-releasing semiochemicals, as either repellents or attractants, may be highly efficacious for pest biocontrol and can significantly increase tea yields. Furthermore, the start date of applying semiochemicals can be optimized to effectively increase tea yields. The current model qualitatively characterizes key features of the tritrophic interactions and provides critical insight into pest control in tea ecosystems.

TGF-ß regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection.

Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-ß in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-ß signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-ß regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-ß also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-ß signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.

SMAD4 and TGFß are architects of inverse genetic programs during fate determination of antiviral CTLs.

Transforming growth factor ß (TGFß) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. For this study, genetically modified mice were used to determine how SMAD4 and TGFß receptor II (TGFßRII) participate in transcriptional programming of pathogen-specific CTLs. We show that these molecules are essential components of opposing signaling mechanisms, and cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissues. TGFß uses a canonical SMAD-dependent signaling pathway to downregulate Eomesodermin (EOMES), KLRG1, and CD62L, while CD103 is induced. Conversely, in vivo and in vitro data show that EOMES, KLRG1, CX3CR1, and CD62L are positively regulated via SMAD4, while CD103 and Hobit are downregulated. Intravascular staining also shows that signaling via SMAD4 promotes formation of long-lived terminally differentiated CTLs that localize in the vasculature. Our data show that inflammatory molecules play a key role in lineage determination of pathogen-specific CTLs, and use SMAD-dependent signaling to alter the expression levels of multiple homing receptors and transcription factors with known functions during memory formation.