Deep profiling deconstructs features associated with memory CD8 T cell tissue residence.

Tissue-resident memory CD8 T (Trm) cells control infections and cancer and are defined by their lack of recirculation. Because migration is difficult to assess, residence is usually inferred by putative residence-defining phenotypic and gene signature proxies. We assessed the validity and universality of residence proxies by integrating mouse parabiosis, multi-organ sampling, intravascular staining, acute and chronic infection models, dirty mice, and single-cell multi-omics.

Corticotropin-Releasing Factor Release From a Unique Subpopulation of Accumbal Neurons Constrains Action-Outcome Acquisition in Reward Learning.

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin-releasing factor (CRF) has been previously documented.

CRF release from a unique subpopulation of accumbal neurons constrains action-outcome acquisition in reward learning.

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin releasing factor (CRF) has been previously documented.

Cutting Edge: First Lung Infection Permanently Enlarges Lymph Nodes and Enhances New T Cell Responses.

Humans experience frequent respiratory infections. Immunology and vaccinology studies in mice are typically performed in naive specific pathogen-free animals responding to their very first respiratory challenge. We found that the first respiratory infection induces lifelong enlargement of the lung-draining mediastinal lymph nodes (medLNs).

Depleting CD103+ resident memory T cells in vivo reveals immunostimulatory functions in oral mucosa.

The oral mucosa is a frontline for microbial exposure and juxtaposes several unique tissues and mechanical structures. Based on parabiotic surgery of mice receiving systemic viral infections or co-housing with microbially diverse pet shop mice, we report that the oral mucosa harbors CD8+ CD103+ resident memory T cells (TRM), which locally survey tissues without recirculating. Oral antigen re-encounter during the effector phase of immune responses potentiated TRM establishment within tongue, gums, palate, and cheek.

Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells.

Respiratory tract resident memory T cells (T), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory T. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles.

Thalamocortical axons regulate neurogenesis and laminar fates in the early sensory cortex.

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons are required for the production and specification of the proper number of layer 4 neurons in primary sensory areas by the neonatal stage.

Action errors impair active working memory maintenance.

The ability to detect and correct action errors is paramount to safe and efficient behavior. Its underlying processes are subject of intense scientific debate. The recent adaptive orienting theory of error processing (AOT) proposes that errors trigger a cascade of processes that purportedly begins with a broad suppression of active motoric and-crucially-cognitive processes.

Mice with diverse microbial exposure histories as a model for preclinical vaccine testing.

Laboratory mice comprise an expeditious model for preclinical vaccine testing; however, vaccine immunogenicity in these models often inadequately translates to humans. Reconstituting physiologic microbial experience to specific pathogen-free (SPF) mice induces durable immunological changes that better recapitulate human immunity. We examined whether mice with diverse microbial experience better model human responses post vaccination.

Cutting Edge: Nucleocapsid Vaccine Elicits Spike-Independent SARS-CoV-2 Protective Immunity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing Abs target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants.

Nucleocapsid vaccine elicits spike-independent SARS-CoV-2 protective immunity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing antibodies target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants.

Expansible residence decentralizes immune homeostasis.

In metazoans, specific tasks are relegated to dedicated organs that are established early in development, occupy discrete locations and typically remain fixed in size. The adult immune system arises from a centralized haematopoietic niche that maintains self-renewing potential, and-upon maturation-becomes distributed throughout the body to monitor environmental perturbations, regulate tissue homeostasis and mediate organism-wide defence. Here we examine how immunity is integrated within adult mouse tissues, and address issues of durability, expansibility and contributions to organ cellularity.

Cutting Edge: Mouse SARS-CoV-2 Epitope Reveals Infection and Vaccine-Elicited CD8 T Cell Responses.

The magnitude of SARS-CoV-2-specific T cell responses correlates inversely with human disease severity, suggesting T cell involvement in primary control. Whereas many COVID-19 vaccines focus on establishing humoral immunity to viral spike protein, vaccine-elicited T cell immunity may bolster durable protection or cross-reactivity with viral variants. To better enable mechanistic and vaccination studies in mice, we identified a dominant CD8 T cell SARS-CoV-2 nucleoprotein epitope.

Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection.

Numerous observations indicate that resident memory T cells (TRM) undergo unusually rapid attrition within the lung. Here we demonstrate that contraction of lung CD8+ T cell responses after influenza infection is contemporized with egress of CD69+/CD103+ CD8+ T cells to the draining mediastinal LN via the lymphatic vessels, which we term retrograde migration. Cells within the draining LN retained canonical markers of lung TRM, including CD103 and CD69, lacked Ly6C expression (also a feature of lung TRM), maintained granzyme B expression, and did not equilibrate among immunized parabiotic mice.

Integrating resident memory into T cell differentiation models.

Advances in the field of T cell memory, including the discovery of tissue residency, continue to add to the list of defined T cell subsets. Here, we briefly review the role of resident memory T cells (T) in protective immunity, and propose that they exhibit developmental and migrational plasticity. We discuss T cell classification, the concept of cell type versus 'subset', and the difficulty of inferring developmental relationships between cells occupying malleable differentiation states.

Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy.

The immunosuppressive tumor microenvironment limits the success of current immunotherapies. The host retains memory T cells specific for previous infections throughout the entire body that are capable of executing potent and immediate immunostimulatory functions. Here we show that virus-specific memory T cells extend their surveillance to mouse and human tumors.

Tissue-resident memory T cells live off the fat of the land.

The consumption of exogenous free fatty acids by tissue-resident memory T (Trm) cells is critical for their long-term survival and antiviral function, and appears to be a conserved feature of Trm cells in both mouse and man, a recent paper published in Nature demonstrates.

A 33D1+ Dendritic Cell/Autoreactive CD4+ T Cell Circuit Maintains IL-2-Dependent Regulatory T Cells in the Spleen.

Phenotypically and functionally diverse regulatory T (Tr) cell subsets populate lymphoid and nonlymphoid tissues, where their maintenance and function are governed by unique homeostatic signals. Whereas Tr cells resident in nonlymphoid tissues depend on continual TCR signaling for their survival and function, phenotypically naive Tr cells occupying secondary lymphoid organs are largely supported by paracrine IL-2 signaling. Crucially, the absence of either of these distinct Tr cell subsets results in pathogenic autoimmunity, underscoring their nonredundant roles in the preservation of self-tolerance.

Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation.

Regulatory T (Treg) cells play a vital role in the prevention of autoimmunity and the maintenance of self-tolerance, but these cells also have an active role in inhibiting immune responses during viral, bacterial, and parasitic infections. Although excessive Treg activity can lead to immunodeficiency, chronic infection, and cancer, too little Treg activity results in autoimmunity and immunopathology and impairs the quality of pathogen-specific responses. Recent studies have helped define the homeostatic mechanisms that support the diverse pool of peripheral Treg cells under steady-state conditions and delineate how the abundance and function of Treg cells changes during inflammation.

Increased surfactant protein D fails to improve bacterial clearance and inflammation in serpinB1-/- mice.

Previously, we described the protective role of the neutrophil serine protease inhibitor serpinB1 in preventing early mortality of Pseudomonas aeruginosa lung infection by fostering bacterial clearance and limiting inflammatory cytokines and proteolytic damage. Surfactant protein D (SP-D), which maintains the antiinflammatory pulmonary environment and mediates bacterial removal, was degraded in infected serpinB1-deficient mice. Based on the hypothesis that increased SP-D would rescue or mitigate the pathological effects of serpinB1 deletion, we generated two serpinB1(-/-) lines overexpressing lung-specific rat SP-D and inoculated the mice with P.

A serpinB1 regulatory mechanism is essential for restricting neutrophil extracellular trap generation.

NETosis (neutrophil extracellular trap [NET] generation), a programmed death pathway initiated in mature neutrophils by pathogens and inflammatory mediators, can be a protective process that sequesters microbes and prevents spread of infection, but it can also be a pathological process that causes inflammation and serious tissue injury. Little is known about the regulatory mechanism. Previously, we demonstrated that serpinb1-deficient mice are highly susceptible to pulmonary bacterial and viral infections due to inflammation and tissue injury associated with increased neutrophilic death.

SerpinB1 protects the mature neutrophil reserve in the bone marrow.

SerpinB1 is among the most efficient inhibitors of neutrophil serine proteases--NE, CG, and PR-3--and we investigated here its role in neutrophil development and homeostasis. We found that serpinB1 is expressed in all human bone marrow leukocytes, including stem and progenitor cells. Expression levels were highest in the neutrophil lineage and peaked at the promyelocyte stage, coincident with the production and packaging of the target proteases.

Start a freestanding emergency center.

Community need sparked the concept for a freestanding emergency center. Key first steps: new legislation, construction, and education.

Managing cognitive impairment in the elderly: conceptual, intervention and methodological issues.

Purpose: With the aging of society, the incidence of dementia in the elderly is also increasing, and thus results in increased numbers of individuals with cognitive impairment. Nurses and other researchers have investigated issues concerning the management of cognitive impairment. This article highlights conceptual, intervention and methodological issues associated with this phenomenon.