Search

Following their activation and expansion in response to foreign threats, many T cells are retained in peripheral tissues without recirculating in the blood. These tissue-resident CD8+ memory T (T RM) cells patrol barrier surfaces and nonlymphoid organs, where their critical role in protecting against viral and bacterial infections is well established. Recent evidence suggests that T RM cells also play a vital part in preventing the development and spread of solid tumors. Here, we discuss the emerging role of T RM cells in anticancer immunity. We highlight defining features of tumor-localizing T RM cells, examine the mechanisms through which they have recently been shown to suppress cancer growth, and explore their potential as future targets of cancer immunotherapy. T RM cells are non-recirculating immune cells that reside in peripheral tissues where they can protect against local infections and cancer. CD69+CD103+ T RM -like cells accumulate in various human solid cancers where they have been associated with improved disease outcomes and patient survival. Vaccine-generated T RM cells can protect against tumor challenge independently of T CIRC cells. T RM cells may mediate tumor protection by promoting tumor-immune equilibrium through the secretion of cytokines and/or via CD103-enhanced tumor cell killing. T RM cells express inhibitory checkpoint molecules and may serve as potential targets for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

CD4+ T cells exhibit diverse functions in cancer surveillance. Concordantly, single-cell transcriptional analyses have revealed several distinct CD4+ T-cell differentiation states in tumours, including cytotoxic and regulatory subsets associated with favourable or unfavourable outcomes, respectively. These transcriptional states are determined and further shaped by dynamic interactions of CD4+ T cells with different types of immune cells, stromal cells and cancer cells. Therefore, we discuss the cellular networks in the tumour microenvironment (TME) that either promote or impede CD4+ T-cell cancer surveillance. We consider antigen/Major histocompatibility complexclass-II (MHC-II)-dependent interactions of CD4+ T cells with both professional antigen-presenting cells and cancer cells, the latter of which can directly express MHC-II, at least in some tumours. Additionally, we examine recent single-cell RNA sequencing studies that have shed light on the phenotype and functions of cancer-specific CD4+ T cells in human tumours. • Single-cell RNA sequencing has identified cancer-specific CD4+ T- cell transcriptional states. • T-cell states can be regulated upon antigen stimulation within the TME. • The consequence of CD4+ T cells directly binding MHC-II+ cancer cells may be context-dependent. [ABSTRACT FROM AUTHOR]

Summary: A large proportion of memory T cells disseminated throughout the body are non‐recirculating cells whose maintenance and function is regulated by tissue‐specific environmental cues. These sessile cells are referred to as tissue‐resident memory T (TRM) cells and similar populations of non‐recirculating cells also exist among unconventional T cells and innate lymphocyte cells. The pool of TRM cells is highly diverse with respect to anatomical positioning, phenotype, molecular regulation and effector function. Nevertheless, certain transcriptional programs are shared and appear as important unifying features for the overall population of TRM cells and tissue‐resident lymphocytes. It is now widely appreciated that TRM cells are a critical component of our immune defense by acting as peripheral sentinels capable of rapidly mobilizing protective tissue immunity upon pathogen recognition. This function is of particular importance in anatomical sites that are not effectively surveilled by blood‐borne memory T cells in absence of inflammation, such as neuronal tissues or epithelial compartments in skin and mucosae. Focusing on the well‐characterized subtype of CD8+ CD69+ CD103+ TRM cells, we will review current concepts on the generation, persistence and function of TRM cells and will summarize commonly used tools to study these cells. Furthermore, we will discuss accumulating data that emphasize localized TRM responses as an important determinant of tissue homeostasis and immune defense in the context of microbiota‐immune interactions, persistent infections and cancer surveillance. [ABSTRACT FROM AUTHOR]

Water vapor is an important constituent in the earth's atmosphere that must be understood to predict weather and climate. Water vapor is challenging to measure, and observations of water vapor must be as independent of weather and climate models as possible in order to assess and improve those models. When combined with independent atmospheric temperature estimates, GPS radio occultation (RO) refractivity profiles yield unique, all-weather, high-vertical-resolution, globally distributed profiles of tropospheric water vapor whose vertical extent is maximum at low latitudes. A method for retrieving water vapor, known as the direct method, combines GPS RO-derived refractivity with temperatures from global weather analyses. Unlike variational methods, the direct method does not use the water vapor estimates from analyses because of their potential systematic errors. While utilization of the direct method has been limited because it produces negative values, these unphysical negative values reveal unique information about errors. A deconvolution technique is presented here that uses the negative values to estimate and remove random errors in histograms of water vapor derived via the direct method. Results indicate direct method specific humidity errors at low latitudes range from 0.4 g kg−1 at 725 hPa to 0.14 g kg−1 near 350 hPa, which can be removed via deconvolution. The deconvolved histograms extend to about the 240-K level in the troposphere, corresponding to 10 km at low latitudes. Unlike the limited information of low-order statistical moments like means and variances, histograms capture the full range of variability, which opens a new window into water vapor behavior and increases understanding of processes at work in the hydrological cycle. [ABSTRACT FROM AUTHOR]

The Hippo pathway limits organ size and suppresses tumors. Reporting in Cell , Moroishi et al. (2016) , show that, paradoxically, Hippo pathway inactivation can repress tumor growth by modulating tumor immunogenicity. This could explain the rarity of pathway mutations in cancers and suggests Hippo pathway repression as a cancer immunotherapy modality. [ABSTRACT FROM AUTHOR]

Tissues such as the skin and mucosae are frequendy exposed to microbial pathogens. Infectious agents must be quickly and efficiendy controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, en-sures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell num-bers together with altered migratory patterns of memory T cells can gready improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tis-sues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4+ and CD8+ T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer. [ABSTRACT FROM AUTHOR]

T cell immunity has long been described in terms of two circulating memory populations. Central memory T (TCM) cells migrate between the secondary lymphoid organs and are capable of mounting a recall proliferative response on pathogen re-encounter, whereas effector memory T (TEM) cells traffic between blood and extralymphoid compartments for effective peripheral immune surveillance. It is now clear that there exists a third category of memory cells that never returns to the circulation. These tissue-resident memory T (TRM) cells are phenotypically distinct from TEM cells, persist in elevated numbers in areas involved in prior infection and have been implicated in various immune phenomena, such as the control of persisting infections and immune disorders in fixed regions of the body. [Copyright &y& Elsevier]

Abstract: This paper provides an overview of modern alloy development, from discovery and optimization towards alloy design, based on combinatorial thin film materials science. The combinatorial approach, combining combinatorial materials synthesis of thin film composition-spreads with high-throughput property characterization has proven to be a powerful tool to delineate composition–structure–property relationships, and hence to efficiently identify composition windows with enhanced properties. Furthermore, and most importantly for alloy design, theoretical models and hypotheses can be critically appraised. Examples for alloy discovery, optimization, and alloy design of functional as well as structural materials are presented. Using Fe-Mn based alloys as an example, we show that the combination of modern electronic-structure calculations with the highly efficient combinatorial thin film composition-spread method constitutes an effective tool for knowledge-based alloy design. [Copyright &y& Elsevier]

Infections localized to peripheral tissues such as the skin result in the priming of T-cell responses that act to control pathogens. Activated T cells undergo migrational imprinting within the draining lymph nodes, resulting in memory T cells that provide local and systemic protection. Combinations of migrating and resident memory T cells have been implicated in long-term peripheral immunity, especially at the surfaces that form pathogen entry points into the body. However, T-cell immunity consists of separate CD4+ helper T cells and CD8+ killer T cells, with distinct effector and memory programming requirements. Whether these subsets also differ in their ability to form a migrating pool involved in peripheral immunosurveillance or a separate resident population responsible for local infection control has not been explored. Here, using mice, we show key differences in the migration and tissue localization of memory CD4+ and CD8+ T cells following infection of the skin by herpes simplex virus. On resolution of infection, the skin contained two distinct virus-specific memory subsets; a slow-moving population of sequestered CD8+ T cells that were resident in the epidermis and confined largely to the original site of infection, and a dynamic population of CD4+ T cells that trafficked rapidly through the dermis as part of a wider recirculation pattern. Unique homing-molecule expression by recirculating CD4+ T effector-memory cells mirrored their preferential skin-migratory capacity. Overall, these results identify a complexity in memory T-cell migration, illuminating previously unappreciated differences between the CD4+ and CD8+ subsets. [ABSTRACT FROM AUTHOR]

Abstract: We have studied the influence of Al and Si additions on the elastic properties of face-centered cubic (fcc) Fe–Mn random alloys with Fe/Mn ratios of 4.00 and 2.33 using ab initio calculations. When Al is added up to 8at.% the shearing elastic constants (C 11–C 12)/2 and C 44 decrease, resulting in a drop of ∼20% in shear and ∼19% in Young’s modulus. In fcc Fe–Mn–Si alloys, the trends in the elastic constants are similar, but less drastic, with a ∼7% shear and ∼6% Young’s modulus decrease when Si is added up to 8at.%. The Fe/Mn ratio exhibits a minor influence on the shear and Young’s modulus values at constant Al and Si contents. To assess the quality of the ab initio data Fe–Mn–Al and Fe–Mn–Si thin films with an fcc structure were combinatorially synthesized and the elastic properties measured using nanoindentation. For both systems the measured and calculated lattice parameters are in good agreement. Although the measured Young’s modulus data showed significant scatter due to the high surface roughness, they are in good agreement with the predicted values. For the Fe–Mn–Al system the calculations generally underestimate the experimental data by ∼15%. For the Fe–Mn–Si system the calculated data are in general lower by ∼10% than the experimentally determined values. The presented results are of relevance for multicomponent alloy design, since the effect of Si and Al addition on the elastic properties of Fe–Mn alloys can be predicted based on ab initio data. [Copyright &y& Elsevier]

Effective viral immunity depends on the activation of T cells by professional antigen presenting cells, such as dendritic cells (DC). The remarkable heterogeneity of the DC network allows the immune system to respond specifically to various infection strategies by different viruses. As a consequence, DC-T cell interactions resulting in optimal virus-specific T cell priming are highly flexible and involve different types of DC. Further highlighting this complexity, recent lines of evidence suggest that presentation of viral antigen by DC is not only restricted to lymphoid organs, but instead also occurs at peripheral sites of infection. Here we discuss the multifaceted interactions between DC and T cells during peripheral virus infections in both lymphoid organs and the periphery. [Copyright &y& Elsevier]

Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an example of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry. [ABSTRACT FROM AUTHOR]

Continuous single-crystal α-Al2O3 fibers were coated with Ni45Al45Cr7.5Ta2.5 (IP75) alloy by physical vapor deposition (PVD). The strength of the coated fibers was evaluated by tensile testing and compared with the strength of uncoated fibers. The effect of temperature during diffusion bonding as well as the presence of a BN interlayer deposited by chemical vapor deposition (CVD) on the fiber strength was studied. Fibers coated with IP75, but without a BN interlayer, retained 23% of their initial strength after the PVD process and fractured during heat treatment. Evidence for thermal stress induced twin formation is presented. Fibers coated with a BN interlayer retained their initial strength during the coating processes. However, only 13% of their initial strength could be retained after the heat treatment. Here, chemical reactions cause morphological changes of the fiber surface. These may act as stress concentration sites, resulting in the extensive strength reduction reported here. These data are important for formulating future strategies avoiding or minimizing strength degradation during production of intermetallic matrix composites. [ABSTRACT FROM AUTHOR]

Abstract. The authors report on the effects of a university and community coalition in preventing problems related to college students' off-campus drinking. The Albany, New York, Committee on University and Community Relations used strategies based on an environmental-management approach that focuses on changing the environment in which individuals make decisions about alcohol consumption and related behaviors. Committee initiatives included improving enforcement of local laws and ordinances, creating a safety-awareness campaign for off-campus students, and developing a comprehensive advertising and beverage-service agreement with local tavern owners. The initiatives were associated with a decline in the number of alcohol-related problems in the community, as indicated by decreases in the number of off-campus noise ordinance reports filed by police and the number of calls to a university-maintained hotline for reporting off-campus problems. An environmental management approach, the authors suggest, has promise as an effective means of preventing alcohol-related problems among college students. [ABSTRACT FROM AUTHOR]

The stability of time modulated Taylor-Couette flow with co- and counter-rotating cylinders and modulated inner cylinder velocity is investigated. The mean velocities of the inner and outer cylinders are chosen to be in constant relative distance to the stability border of nonmodulated Taylor-Couette flow and the inner cylinder velocity is periodically modulated. The critical modulation amplitude, which leads to linear instability of the modulated laminar flow, is calculated with numerically integrated Floquet theory, as well as with perturbation theory. The critical modulation amplitude as a function of the outer cylinder Reynolds number has a richstructure for counter-rotating cylinders, which is open to experimental test. The critical modulation amplitude decreases monotonically with increasing rotation frequency for corotating cylinders. [ABSTRACT FROM AUTHOR]

The article focuses on a study published in the periodical which showed that memory T cells have an important role in tissue pathology and are major determinants of hypersensitive reactions. Topics discussed include high-throughput sequencing for tracking T cell clones, ear-swelling caused by memory T cells when treated with 1-fluoro-2,4-dinitrobenzene (DNFB) and clarifying role of killer and helper T cells in skin inflammatory responses.

The article discusses three reports within the issue on immunology research, including one by N. Iijima and A. Iwasaki, one by J. M. Schenkel et al., and one by S. Ariotti et al., investigating the molecular mechanisms underlying the persistence and protective function of tissue-resident memory T cells (TRM). Topics include CD4 TRM cell retention, TRM cell activation, and infection control involving the cytokine interferon-γ (IFN-γ).

CD8+ T cells recognizing different classes of tumor-derived antigens display a strong yet not absolute bias toward dysfunction-related phenotypes. Thus, tumor-reactive CD8 SP + sp T cells displayed a strong bias toward exhaustion-associated transcriptional profiles, although this link was not absolute, as most tumor-specific TCRs were also expressed by a minor portion of cells with memory-associated transcriptomes. [Extracted from the article]

Herein, we demonstrate "direct" 13C hyperpolarization of 13C‐acetate via signal amplification by reversible exchange (SABRE). The standard SABRE homogeneous catalyst [Ir‐IMes; [IrCl(COD)(IMes)], (IMes=1,3‐bis(2,4,6‐trimethylphenyl), imidazole‐2‐ylidene; COD=cyclooctadiene)] was first activated in the presence of an auxiliary substrate (pyridine) in alcohol. Following addition of sodium 1‐13C‐acetate, parahydrogen bubbling within a microtesla magnetic field (i.e. under conditions of SABRE in shield enables alignment transfer to heteronuclei, SABRE‐SHEATH) resulted in positive enhancements of up to ≈100‐fold in the 13C NMR signal compared to thermal equilibrium at 9.4 T. The present results are consistent with a mechanism of "direct" transfer of spin order from parahydrogen to 13C spins of acetate weakly bound to the catalyst, under conditions of fast exchange with respect to the 13C acetate resonance, but we find that relaxation dynamics at microtesla fields alter the optimal matching from the traditional SABRE‐SHEATH picture. Further development of this approach could lead to new ways to rapidly, cheaply, and simply hyperpolarize a broad range of substrates (e.g. metabolites with carboxyl groups) for various applications, including biomedical NMR and MRI of cellular and in vivo metabolism. [ABSTRACT FROM AUTHOR]

Herein, we demonstrate "direct" 13C hyperpolarization of 13C‐acetate via signal amplification by reversible exchange (SABRE). The standard SABRE homogeneous catalyst [Ir‐IMes; [IrCl(COD)(IMes)], (IMes=1,3‐bis(2,4,6‐trimethylphenyl), imidazole‐2‐ylidene; COD=cyclooctadiene)] was first activated in the presence of an auxiliary substrate (pyridine) in alcohol. Following addition of sodium 1‐13C‐acetate, parahydrogen bubbling within a microtesla magnetic field (i.e. under conditions of SABRE in shield enables alignment transfer to heteronuclei, SABRE‐SHEATH) resulted in positive enhancements of up to ≈100‐fold in the 13C NMR signal compared to thermal equilibrium at 9.4 T. The present results are consistent with a mechanism of "direct" transfer of spin order from parahydrogen to 13C spins of acetate weakly bound to the catalyst, under conditions of fast exchange with respect to the 13C acetate resonance, but we find that relaxation dynamics at microtesla fields alter the optimal matching from the traditional SABRE‐SHEATH picture. Further development of this approach could lead to new ways to rapidly, cheaply, and simply hyperpolarize a broad range of substrates (e.g. metabolites with carboxyl groups) for various applications, including biomedical NMR and MRI of cellular and in vivo metabolism. [ABSTRACT FROM AUTHOR]

The article presents a study which discusses the immune surveillance by skin resident T cells in human herpes simplex virus (HSV)-2 infection. The study uses collected sequential skin biopsies taken during HSV-2 ulceration to study the phenotype and function of frontline T cells. Results show that frontline T cells represent a distinct type of memory T cells at sites of virus recurrence to prevent containment of lesion development.

The article examines the role of Cytotoxic T lymphocytes (CTL) in the immune system. It states that the said killer T cells are effective in the body's defence against a range of viral, bacterial and parasitic infections. It suggests that the presence of these killer cells in the circulation might be sufficient for their entry into infected tissues. It cites a study in which the researchers have argued that the simple presence of CTLs in the circulation can no longer be considered a guarantee to their access to peripheral locations for successful infection control.

At the same time, T SB RM sb cells may recognize a broad array of stress molecules which are likely to be expressed at elevated levels by virus-infected SCC cells, including the NKG2D ligands MICA (human) and Rae-1 (mouse). Therefore, T SB RM sb cell-mediated protection may at least in part be a result of direct recognition of virus-infected cancer cells, explaining the apparent selection of virus-negative escape variants during eventual SCC development. [Extracted from the article]

Tissue‐resident memory T (TRM) cells occupy peripheral and lymphoid tissues where they confer protection against local infection. While epithelial CD8+ TRM cells coexpress CD69 and CD103, CD103− memory cells have been described in various organs and are often presumed non‐recirculating based on their expression of CD69. We found that both CD69+CD103+ and CD69+CD103− memory cells populated the thymus upon transfer of CD8+ effector T cells into uninfected recipients. Transcriptionally and phenotypically, CD103+ thymic cells resembled non‐lymphoid TRM cells, whereas CD69+CD103− cells displayed a profile that was more closely related to recirculating cells. Although CD69 was required for optimal CD103+ TRM formation, its expression alone did not identify permanently resident cells, as CD69+CD103− cells disappeared from the thymus following antibody‐mediated depletion of recirculating cells. Our findings highlight a distinct migration potential of phenotypically divergent thymic CD8+ memory T cells and emphasise the inadequacy of CD69 as a marker of tissue residency. [ABSTRACT FROM AUTHOR]

Recent clinical studies show activating multiple innate immune pathways drives robust responses in infection and cancer. Biomaterials offer useful features to deliver multiple cargos, but add translational complexity and intrinsic immune signatures that complicate rational design. Here a modular adjuvant platform is created using self‐assembly to build nanostructured capsules comprised entirely of antigens and multiple classes of toll‐like receptor agonists (TLRas). These assemblies sequester TLR to endolysosomes, allowing programmable control over the relative signaling levels transduced through these receptors. Strikingly, this combinatorial control of innate signaling can generate divergent antigen‐specific responses against a particular antigen. These assemblies drive reorganization of lymph node stroma to a pro‐immune microenvironment, expanding antigen‐specific T cells. Excitingly, assemblies built from antigen and multiple TLRas enhance T cell function and antitumor efficacy compared to ad‐mixed formulations or capsules with a single TLRa. Finally, capsules built from a clinically relevant human melanoma antigen and up to three TLRa classes enable simultaneous control of signal transduction across each pathway. This creates a facile adjuvant design platform to tailor signaling for vaccines and immunotherapies without using carrier components. The modular nature supports precision juxtaposition of antigen with agonists relevant for several innate receptor families, such as toll, STING, NOD, and RIG. [ABSTRACT FROM AUTHOR]

The article introduces scientific conference papers on T cells and skin to be presented at the 22nd Scientific meeting 2014 of the Fondation René Touraine (FRT), a European non-governmental organization that promotes therapeutic progress in dermatology, on 5th December 2014 in Paris, France. Papers by researchers Shimon Sakaguchi, Federica Sallusto and Thomas Gebhardt are included. Specific topics include immune abnormalities found in atopic dermatitis and adoptive transfer of dendritic cells.

Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-? (IFN-?) secretion by noncognate memory CD8+ T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8?+ DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1?, only IL-18 was required for IFN-? production by memory CD8+ T cells. Conversely, only the release of IL-1?, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity. [ABSTRACT FROM AUTHOR]

During an initial encounter with herpes simplex virus type 1 (HSV-1) it takes several days for an adaptive immune response to develop and for herpes-specific CD8+ T cells to infiltrate sites of infection. By this time the virus has firmly established itself within the innervating sensory nervous system where it then persists indefinitely. Preventing the establishment of viral latency would require blocking the skin to nervous system transmission of the virus. We wished to examine if CD8+ T cells present early during acute HSV-1 infection could block this transmission. We show that effector CD8+ T cells failed to prevent the establishment of HSV latency even when present prior to infection. This lack of blocking likely reflects the delayed infiltration of the CD8+ T cells into the infected skin. Examination of the kinetics of HSV-1 infection highlighted the rapidity at which the virus infects the sensory ganglia and singled out early viral replication within the skin as an important factor in determining the magnitude of the ensuing latent infection. Though unable to prevent the establishment of latency, CD8+ T cells could reduce the average viral copy number of the residual latent infection by dampening the skin infection and thus limiting the skin-to-nerve transmission of virus.Immunology and Cell Biology (2008) 86, 666–675; doi:10.1038/icb.2008.47; published online 8 July 2008 [ABSTRACT FROM AUTHOR]

Abstract: Despite a continuously growing body of evidence highlighting the role of NPY in the immune system, surprisingly little is known about its ability to alter human leukocyte function. We therefore set out to examine NPY receptor expression and functional effects of NPY in freshly isolated human neutrophils. Our results not only demonstrate for the first time the presence of specific NPY receptors on human neutrophils, but also unveil of how these receptors differentially modulate critical functions of neutrophils such as phagocytosis of bacteria as well as the release of reactive oxygen species. [Copyright &y& Elsevier]

Abstract: Although it is broadly accepted that the immune system and the nervous system functionally interact with each other at various levels, many aspects of this crosstalk still remain unclear. One player in this interaction is neuropeptide Y (NPY), a sympathetic neurotransmitter, which has been demonstrated to regulate a broad variety of immune functions. In this review we will outline key findings on the effects NPY exerts on phagocytosis by neutrophils and monocytes/macrophages and its relevance to the elimination of invading pathogens. Furthermore, we will discuss the implications of these findings for antigen presentation by dendritic cells and the induction of adaptive immune responses. [Copyright &y& Elsevier]

While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4+ T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium (S. Typhimurium) strains carried a pool of IFN-γ+ CD4+ T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella-reactive CD4+ T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4+ T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4+ T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella-specific CD4+ T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections. Author summary: Helper T cells are essential for controlling infections by bacterial pathogens, such as Salmonella enterica var Typhimurium (S. Typhimurium). While it is well-established that this role is related to their provision of IFN-γ, when and where helper T cells elicit their protective function in vivo remains unresolved. We identified a protective helper T cell population in the circulation of mice early after inoculation with growth-attenuated S. Typhimurium strains; this population waned overtime. We observed that circulating helper T cell immunity can adoptively protect naïve recipient mice against lethal S. Typhimurium infection when harvested from a short time-window. In comparing helper T cell responses between spleen and liver in Salmonella-infected mice, we have observed a previously uncharacterized trafficking of helper T cells to the liver followed by the residence of S. Typhimurium-specific T cell memory in the organ. Taken together these findings identify that protective immunity to Salmonella infections is transient in the circulation and the liver as a preferential site of helper T memory cells. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) play a critical role in immune regulation and peripheral tolerance. While different types of Tregs have been identified in both mice and humans, much of our understanding about how these cells maintain immune homeostasis is derived from animal models. In this study, we examined two distinct human lymphoid organs to understand how repeated exposure to infections at the mucosal surface influences the phenotype and tissue localization of Tregs. We show that while Tregs in both tonsils and spleen express a tissue‐resident phenotype, they accumulate in greater numbers in tonsils. Tonsillar‐resident Tregs exhibit a highly suppressive phenotype with significantly increased expression of CD39, ICOS and CTLA‐4 compared with their counterparts in circulation or in the spleen. Functionally, resident Tregs are able effectively to suppress T cell proliferation. We further demonstrate that tonsillar‐resident Tregs share key features of T follicular helper cells. Spatial analysis reveals that the vast majority of resident Tregs are localized at the border of the T‐zone and B cell follicle, as well as within the lymphocyte pockets enriched with resident memory T cells. Together our findings suggest that resident Tregs are strategically co‐localized to maintain immune homeostasis at sites of recurrent inflammation. [ABSTRACT FROM AUTHOR]

Sympathetic nervous system (SNS) activation mobilizes blood leukocytes. Under these circumstances, both epinephrine (EPI) and neuropeptide Y (NPY) are released. Therefore, we investigated a possible interaction between these transmitters during leukocyte mobilization, using intravenous catheterization of male adult Lewis rats. Intravenous application of NPY followed by EPI, dose-dependently facilitated, intensified and inhibited EPI-induced leukocytosis with subset-specificity for NK-cells, monocytes, and B-lymphocytes. Pharmacological assessment of NPY receptors involved revealed a Y-1R-mediated inhibition and a Y-5R-mediated facilitation. RT-PCR on peripheral blood mononuclear cells (PBMC) detected Y-1R mRNA only, suggesting direct Y-1R-mediated effects on leukocytes and indirect effects via the Y-5R. Thus, via a specific Y-1R/Y-5R interplay, NPY acts as a neuroimmune co-transmitter in vivo. [Copyright &y& Elsevier]

The adult heart contains macrophages derived from both embryonic and adult bone marrow (BM)-derived precursors. This population diversity prompted us to explore how distinct macrophage subsets localize within the heart, and their relative contributions in cardiac disease. In this study, using the reciprocal expression of Lyve-1 and Ccr2 to distinguish macrophages with distinct origins, we show that, in the steady state, both embryonic (Lyvepos) and BM-derived (Ccr2pos) macrophages populate the major vessels of the heart in mice and humans. However, cardiac macrophage populations are markedly perturbed by inflammation. In a mouse model of Kawasaki disease, BM-derived macrophages preferentially increase during acute cardiac inflammation and selectively accumulate around major cardiac vessels. The accumulation of BM-derived macrophages coincides with the loss of their embryonic counterparts and is an initiating, essential step in the emergence of subsequent cardiac vasculitis in this experimental model. Finally, we demonstrate that the accumulation of Ccr2pos macrophages (and the development of vasculitis) occurs in close proximity to a population of Ccr2 chemokine ligand-producing epicardial cells, suggesting that the epicardium may be involved in localizing inflammation to cardiac vessels. Collectively, our findings identify the perivascular accumulation of BMderived macrophages as pivotal in the pathogenesis of cardiac vasculitis and provide evidence about the mechanisms governing their recruitment to the heart. [ABSTRACT FROM AUTHOR]

Tissue-resident CD8+ memory T (TRM) cells are immune cells that permanently reside at tissue sites where they play an important role in providing rapid protection against reinfection. They are not only phenotypically and functionally distinct from their circulating memory counterparts, but also exhibit a unique transcriptional profile. To date, the local tissue signals required for their development and long-term residency are not well understood. So far, the best-characterised tissue-derived signal is transforming growth factor-β (TGF-β), which has been shown to promote the development of these cells within tissues. In this study, we aimed to determine to what extent the transcriptional signatures of TRM cells from multiple tissues reflects TGF-β imprinting. We activated murine CD8+ T cells, stimulated them in vitro by TGF-β, and profiled their transcriptomes using RNA-seq. Upon comparison, we identified a TGF-β-induced signature of differentially expressed genes between TGF-β-stimulated and -unstimulated cells. Next, we linked this in vitro TGF-β-induced signature to a previously identified in vivo TRM-specific gene set and found considerable (>50%) overlap between the two gene sets, thus showing that a substantial part of the TRM signature can be attributed to TGF-β signalling. Finally, gene set enrichment analysis further revealed that the altered gene signature following TGF-β exposure reflected transcriptional signatures found in TRM cells from both epithelial and non-epithelial tissues. In summary, these findings show that TGF-β has a broad footprint in establishing the residency-specific transcriptional profile of TRM cells, which is detectable in TRM cells from diverse tissues. They further suggest that constitutive TGF-β signaling might be involved for their long-term persistence at tissue sites. [ABSTRACT FROM AUTHOR]

CD4+ T cell responses are crucial for the control of many intracellular pathogens, yet the requirements for their induction are not fully understood. To better understand the role that various dendritic cell (DC) subtypes play in CD4+ T cell priming, we compared in vivo T cell responses to skin inoculation of mice with infectious or UV-inactivated HSV type 1. Localized infection elicited a Th1 response that was primed in skin-draining lymph nodes involving Ag presentation by migratory dermal and lymph node-resident DC. However, expansion and Th1 differentiation was impaired in response to UV-inactivated virus (UV-HSV), and this defect correlated with a restriction of Ag presentation to migratory CD103- dermal DC. A similar differentiation defect was seen in infected mice lacking CD8α+ and CD103+ classical type 1 DC (cDC1). Finally, Th1 differentiation after UV-HSV inoculation was rescued by targeted Ag delivery to CD8α+ and CD103+ cDC1 using an anti-Clec9A Ab construct. This suggests that Ag presentation by cDC1 is crucial for optimal Th1 immunity to HSV type 1 infection and potentially other pathogens of the skin. [ABSTRACT FROM AUTHOR]

While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against Salmonella infection. Using an epitope-tagged vaccine strain of Salmonella, we found that effective protection correlated with expanded Salmonella-specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteristics of tissue residence and did not acquire robust protective immunity. Using a YFP-IFN-γ reporter system, we identified Th1 cells in the liver of immunized mice that displayed markers of tissue residence, including P2X7, ARTC2, LFA-1, and CD101. Adoptive transfer of liver memory cells after ARTC2 blockade increased protection against highly virulent bacteria. Taken together, these data demonstrate that noncirculating memory Th1 cells are a vital component of immunity to Salmonella infection and should be the focus of vaccine strategies. [ABSTRACT FROM AUTHOR]

Resolution of virus infections depends on the priming of virus-specific CD8+ T cells by dendritic cells (DC). While this process requires major histocompatibility complex (MHC) class I-restricted antigen presentation by DC, the relative contribution to CD8+ T cell priming by infected DC is less clear. We have addressed this question in the context of a peripheral infection with herpes simplex virus 1 (HSV). Assessing the endogenous, polyclonal HSV-specific CD8+ T cell response, we found that effective in vivo T cell priming depended on the presence of DC subsets specialized in cross-presentation, while Langerhans cells and plasmacytoid DC were dispensable. Utilizing a novel mouse model that allows for the in vivo elimination of infected DC, we also demonstrated in vivo that this requirement for cross-presenting DC was not related to their infection but instead reflected their capacity to crosspresent HSV-derived antigen. Taking the results together, this study shows that infected DC are not required for effective CD8+ T cell priming during a peripheral virus infection. IMPORTANCE The ability of some DC to present viral antigen to CD8+ T cells without being infected is thought to enable the host to induce killer T cells even when viruses evade or kill infected DC. However, direct experimental in vivo proof for this notion has remained elusive. The work described in this study characterizes the role that different DC play in the induction of virus-specific killer T cell responses and, critically, introduces a novel mouse model that allows for the selective elimination of infected DC in vivo. Our finding that HSV-specific CD8+ T cells can be fully primed in the absence of DC infection shows that cross-presentation by DC is indeed sufficient for effective CD8+ T cell priming during a peripheral virus infection. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T cells (TRM) have been shown to afford superior protection against infection, particularly against pathogens that enter via the epithelial surfaces of the body. Although TRM are often concentrated at sites of prior infection, it has been shown that TRM can disseminate throughout the body. We examined the relative effectiveness of global versus targeted CD8+ TRM lodgment in skin. The site of initial T cell priming made little difference to skin lodgement, whereas local inflammation and Ag recognition enhanced TRM accumulation and retention. Disseminated TRM lodgment was seen with the skin, but required multiple exposures to Ag and was inferior to targeted strategies. As a consequence, active recruitment by inflammation or infection resulted in superior TRM numbers and maximal protection against infection. Overall, these results highlight the potency of localized TRM deposition as a means of pathogen control as well as demonstrating the limitations of global TRM lodgment. [ABSTRACT FROM AUTHOR]

Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103—, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection.To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations. [ABSTRACT FROM AUTHOR]

The ability of CD4 T cells to give rise to specialized T follicular helper cells (TFH) critical to initiating appropriate Ab responses is regulated by environmental cues in lymphoid tissues draining the site of infection. In this study, we used a skin infection with HSV-1 characterized by the successive involvement of interconnected but distinct lymph nodes (LNs), to investigate the anatomical diversification of virus-specific CD4 T cell responses and the migratory capacity of TFH or their precursors. Whereas Th1 effector CD4 T cells expressing peripheral-targeting migration molecules readily migrated from primary to secondary reactive LNs, Bcl6+ CXCR5+ PD1hi TFH were largely retained at the site of initial activation with little spillover into the downstream LNs involved at later stages of infection. Consistent with this, TFH maintained high-level surface expression of CD69, indicative of impaired migratory capacity. Notably, the biased generation and retention of TFH in primary LNs correlated with a preferential generation of germinal centers at this site. Our results highlight a limited anatomical diversification of TFH responses and germinal center reactions that were imprinted within the first few cell divisions during TFH differentiation in LNs draining the site of initial infection. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T cells provide local immune protection in barrier tissues, such as skin and mucosa. However, the molecular mechanisms controlling effector T cell retention and subsequent memory formation in those locations are not fully understood. In this study, we analyzed the role of CD69, an early leukocyte activation marker, in regulating effector T cell egress from peripheral tissues. We provide evidence that CD69 surface expression by skin-infiltrating CD8 T cells can be regulated at multiple levels, including local Ag stimulation and signaling through type I IFNRs, and it coincides with the transcriptional downregulation of the sphingosine-1-phosphate receptor S IP,. Importantly, we demonstrate that expression of CD69, by interfering with sphingosine-1-phosphate receptor function, is a critical determinant of prolonged T cell retention and local memory formation. Our results define an important step in the generation of long-lived adaptive immune memory at body surfaces. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T cells provide local immune protection in barrier tissues, such as skin and mucosa. However, the molecular mechanisms controlling effector T cell retention and subsequent memory formation in those locations are not fully understood. In this study, we analyzed the role of CD69, an early leukocyte activation marker, in regulating effector T cell egress from peripheral tissues. We provide evidence that CD69 surface expression by skin-infiltrating CD8 T cells can be regulated at multiple levels, including local Ag stimulation and signaling through type I IFNRs, and it coincides with the transcriptional downregulation of the sphingosine-1-phosphate receptor SI Pi. Importantly, we demonstrate that expression of CD69, by interfering with sphingosine-1-phosphate receptor function, is a critical determinant of prolonged T cell retention and local memory formation. Our results define an important step in the generation of long-lived adaptive immune memory at body surfaces. [ABSTRACT FROM AUTHOR]

Efficient infection control requires potent T-cell responses at sites of pathogen replication. However, the regulation of T-cell effector function in situ remains poorly understood. Here, we show key differences in the regulation of effector activity between CD4+ and CD8+ T-cells during skin infection with HSV-1. IFN-γ-producing CD4+ T cells disseminated widely throughout the skin and draining lymph nodes (LN), clearly exceeding the epithelial distribution of infectious virus. By contrast, IFN-γ-producing CD8+ T cells were only found within the infected epidermal layer of the skin and associated hair follicles. Mechanistically, while various subsets of lymphoid- and skin-derived dendritic cells (DC) elicited IFN-γ production by CD4+ T cells, CD8+ T cells responded exclusively to infected epidermal cells directly presenting viral antigen. Notably, uninfected cross-presenting DCs from both skin and LNs failed to trigger IFN-γ production by CD8+ T-cells. Thus, we describe a previously unappreciated complexity in the regulation of CD4+ and CD8+ T-cell effector activity that is subset-specific, microanatomically distinct and involves largely non-overlapping types of antigen-presenting cells (APC). [ABSTRACT FROM AUTHOR]

Background: Development and function of tissue resident mast cells (MCs) is tightly controlled by various cytokines, most of which belong to the typical T helper (Th) 2-type cytokines such as IL-3 and IL-4. The effects of the Th1-type cytokine IFN-γ on human MCs is less clear. Results: Here, we analyzed the effects of IFN-γ on tissue-derived, mature human MCs. We found that INF-γ decreases proliferation, without affecting apoptosis in human intestinal MCs cultured in the presence of optimal concentrations of stem cell factor (SCF) or SCF and IL-4. However, in the absence of growth factors or at suboptimal concentrations of SCF, INF-γ promotes survival through inhibition of MC apoptosis. Interestingly, we found that INF-γ has no effect on FcεRI expression and FcεRI-mediated release of histamine and leukotriene (LT)C4, while it has profound effects on FcγR expression and activation. We show that intestinal MCs express FcγRI, FcγRIIa, and FcγRIIc, whereas FcγRIIb expression was found in only 40% of the isolates and FcγRIII was never detectable. INF-γ strongly increases FcγRI and decreases FcγRIIa expression. INF-γ-naïve MCs produce LTC4 but fail to degranulate upon crosslinking of surface-bound monomeric IgG. In contrast, INF-γ-treated MCs rapidly release granule-stored histamine in addition to de novo-synthesized LTC4. Conclusion: In summary, we identify INF-γ as an important regulator of tissue-resident human MCs. IFN-γ displays a dual function by blocking extensive MC proliferation, while decreasing apoptosis in starving MCs and enhancing FcγRI expression and activation. These results emphasize the involvement of mucosal MCs in Th1-mediated disorders. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T cells (TRM cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103+CD8+ TRM cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into TRM cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues. [ABSTRACT FROM AUTHOR]

Highlights: [•] Peripheral tissues contain a complex mixture of migrating and sessile memory T cells. [•] CD103+CD8+ memory T cells are the best characterised type of tissue-resident memory T cells. [•] Recirculating memory T cells (TRCM) may express peripheral as well as lymphoid homing molecules. [•] Memory T cells present in peripheral tissues provide superior local immunity. [Copyright &y& Elsevier]

Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (TRM) cells are identified by their expression of the α-chain from the integrin αE(CD103)β7, and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103+CD8+ TRM cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the TRM phenotype. The CD8+ TRM cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral TRM cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection. [ABSTRACT FROM AUTHOR]