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Ever since the discovery of dendritic cells by Ralph Steinman and Zanvil Cohn in 1973, it is increasingly evident that dendritic cells are integral for adaptive immune responses, and there is an undeniable focus on them for vaccines development. Fungal infections, often thought to be innocuous, are becoming significant threats due to an increased immunocompromised or immune-suppressed population and climate change. Further, the recent COVID-19 pandemic unraveled the wrath of fungal infections and devastating outcomes. Invasive fungal infections cause significant case fatality rates ranging from 20% to 90%. Regrettably, no licensed fungal vaccines exist, and there is an urgent need for preventive and therapeutic purposes. In this review, we discuss the ontogeny, subsets, tissue distribution, and functions of lung dendritic cells. In the latter part, we summarize and discuss the studies on the DC-based vaccines against pulmonary fungal infections. Finally, we highlight some emerging potential avenues that can be incorporated for DC-based vaccines against fungal infections. [ABSTRACT FROM AUTHOR]

Individuals who are immunocompromised, including AIDS patients with few CD [4.sup.+] T cells, are at increased risk for opportunistic fungal infections. The incidence of such infections is increasing worldwide, meaning that the need for antifungal vaccines is increasing. Although CD [4.sup.+] T cells play a dominant role in resistance to many pathogenic fungal infections, we have previously shown that vaccination can induce protective antifungal CD [8.sup.+] T cell immunity in the absence of CD [4.sup.+] T cells. However, it has not been determined whether vaccine-induced antifungal CD [8.sup.+] T cell memory can be maintained in the absence of CD [4.sup.+] T cell help. Here, we have shown in a mouse model of vaccination against blastomycosis that antifungal memory CD [8.sup.+] T cells are maintained in the absence of CD [4.sup.+] T cells without loss of numbers or function for at least 6 months and that the cells protect against infection. Using a system that enabled us to induce and track antigen-specific, antifungal CD [8.sup.+] T cells, we found that such cells were maintained for at least 5 months upon transfer into naive mice lacking both CD [4.sup.+] T cells and persistent fungal antigen. Additionally, fungal vaccination induced a profile of transcription factors functionally linked with persistent memory in CD [8.sup.+] T cells. Thus, unlike bacteria and viruses, fungi elicit long-term CD [8.sup.+] T cell memory that is maintained without CD [4.sup.+] T cell help or persistent antigen. This has implications for the development of novel antifungal vaccine strategies effective in immunocompromised patients., Introduction The mounting incidence of opportunistic fungal infections in immunocompromised hosts, including AIDS patients, is of great medical importance (1, 2). Infected patients may receive toxic antifungal drugs over an [...]

IL-7 is integral to the generation and maintenance of [CD8.sup.+] T cell memory, and insufficient IL-7 is believed to limit survival and the persistence of memory [CD8.sup.+] T cells. Here, we show that during the mouse T cell response to lymphocytic choriomeningitis virus, IL-7 enhanced the number of memory [CD8.sup.+] T cells when its administration was restricted to the contraction phase of the response. Likewise, IL-7 administration during the contraction phase of the mouse T cell response to vaccinia virus or a DNA vaccine potentiated antigen-specific [CD8.sup.+] memory T cell proliferation and function. Qualitatively, [CD8.sup.+] T cells from IL-7-treated mice exhibited superior recall responses and improved viral control. IL-7 treatment during the memory phase stimulated a marked increase in the number of memory [CD8.sup.+] T cells, but the effects were transient. IL-7 therapy during contraction of the secondary [CD8.sup.+] T cell response also expanded the pool of memory [CD8.sup.+] T cells. Collectively, our studies show differential effects of IL-7 on memory [CD8.sup.+] T cell homeostasis and underscore the importance of the timing of IL-7 therapy to effectively improve [CD8.sup.+] T cell memory and protective immunity. These findings may have implications in the clinical use of IL-7 as an immunotherapeutic agent to bolster vaccine-induced [CD8.sup.+] T cell memory., Introduction It is well recognized that CD8 T cells play an important role in defense against several viral, intracellular bacterial, and protozoan infections. Therefore, for vaccines to be effective against [...]

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens affecting the global swine industry. Vaccination is still a main strategy for PRRSV control; however, host factors associated with vaccine efficacy remain poorly understood. Growing evidence suggests that mucosa-associated microbiomes may play a role in the responses to vaccination. In this study, we investigated the effects of a killed virus vaccine on the gut microbiome diversity in pigs. Fecal microbial communities were longitudinally assessed in three groups of pigs (vaccinated/challenged with PRRSV, unvaccinated/challenged with PRRSV, and unvaccinated/unchallenged) before and after vaccination and after viral challenge. We observed significant interaction effects between viral challenge and vaccination on both taxonomic richness and community diversity of the gut microbiota. While some specific taxonomic alterations appear to be enhanced in vaccinated/challenged pigs, others appeared to be more consistent with the levels in control animals (unvaccinated/unchallenged), indicating that vaccination incompletely protects against viral impacts on the microbiome. The abundances of several microbial taxa were further determined to be correlated with the level of viral load and the amount of PRRSV reactive CD4+ and CD8+ T-cells. This study highlights the potential roles of gut microbiota in the response of pigs to vaccination, which may pave the road for the development of novel strategies to enhance vaccine efficacy. [ABSTRACT FROM AUTHOR]

Fungal infections in CD4+ T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8+ T cell responses and immunity to inactivated vaccine in the absence of CD4+ T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8+ T cells in response to inactivated fungal vaccination in a mouse model of CD4+ T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-γ) and type 17 (IL-17A) CD8+ T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb-/- mice. Augmented CD8+ T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and RORγt. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8+ T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8+ T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients. [ABSTRACT FROM AUTHOR]

Highlights: [•] We provide an update on understanding of the immunological mechanisms that underpin vaccine immunity to fungi. [•] We describe new developments concerning vaccines against fungal pathogens in humans. [•] We review the prospects for harnessing protective immune responses against fungi in immune compromised hosts. Only a handful of the many fungal species on our planet cause infections in humans. Despite many medical advances, invasive fungal infections have skyrocketed in recent years and pose a growing health problem in both immune-competent and immune-deficient hosts. Recent strides in our understanding of fungal immunity have raised the prospect that vaccines against fungi can be developed that are effective, safe and able to elicit lasting immunity even in immune deficient individuals. We discuss progress in vaccine development and understanding mechanisms of protection against fungi including in patients with impaired CD4+ T-cell immunity. [Copyright &y& Elsevier]

Simple Summary: Platelet-rich plasma (PRP) is a popular therapy in human and veterinary medicine. This study compared three manual noncommercial methods to prepare PRP and its cooling. The three methods concentrated platelets and did not alter viability. Method 1 (i.e., involving double centrifugation) resulted in the greatest platelet concentrations, while method 3 (sedimentation) resulted in the lowest platelet concentration and greater contamination with white blood cells (WBC). Cooling increased platelet agglutination over time across methods and affected platelet viability in PRP obtained with method 3. It remains unknown whether the different methods and cooling would affect PRP's clinical efficacy. In light of PRP's increasing popularity in veterinary practice, this study aimed to compare three manual methods to prepare and cool equine PRP. The blood of 18 clinically healthy mares was collected via venipuncture in a blood transfusion bag (method 1), blood tubes (method 2), and a syringe (method 3). In method 1, samples were double centrifuged; method 2 involved one centrifugation, and in method 3 the syringe was kept in an upright position to sediment for 4 h. After processing with three methods, PRP and platelet-poor plasma (PPP) were extracted and assessed for red (RBC) and white blood cell counts (WBC), platelet counts, and viability. In a subset of mares (n = 6), samples were processed with the three methods, and PRP was evaluated at 6 and 24 h postcooling at 5 °C. Method 1 resulted in the highest and method 3 in the lowest platelet concentration (p < 0.05), and the latter also had greater contamination with WBC than the others (p < 0.001). Platelet viability was similar across treatments (p > 0.05). Cooling for 24 h did not affect platelet counts in all methods (p > 0.05); however, platelet viability was reduced after cooling PRP produced by method 3 (p = 0.04), and agglutination increased over time in all methods (p < 0.001). The three methods increased (1.8–5.6-fold) platelet concentration in PRP compared to whole blood without compromising platelet viability. In conclusion, all three methods concentrated platelets and while cooling affected their viability. It remains unknown whether the different methods and cooling would affect PRP's clinical efficacy. [ABSTRACT FROM AUTHOR]

Studies in B-cell-deficient mice have indicated that B cells might play an important role in regulating CD8+ T cell responses. The interpretation of experiments in B-cell-deficient mice is complicated due to the abnormal histological architecture of lymphoid organs. Additionally, the role of antigen-specific B cells in regulation of CD8+ T cell responses has not been studied. The B-cell transgenic mice (HEL-ITg), in which all B cells express the antigen receptor for hen egg lysozyme, is an excellent model to study the role of antigen-specific B cells in regulating CD8+ T cell responses without the complication of lymphoid abnormalities associated with B cell knockout mice. In response to an acute infection with lymphocytic choriomeningitis virus (LCMV), HEL-ITg mice mounted a potent primary CD8+ T-cell response. However, the functional and phenotypic maturation of memory CD8+ T cell was adversely affected in HEL-ITg mice. LCMV-specific memory CD8+ T cells were impaired in IL-2 production and exhibited a predominantly CD62Llo/CD127lo phenotype. Additionally, memory CD8+ T cells in HEL-ITg mice provided poor protective immunity to secondary challenge. These studies show that antigenic-specific B cells are essential for optimal CD8 T cell responses to an acute viral infection. Work was supported by a PHS grant to M. Suresh from NIH. [ABSTRACT FROM AUTHOR]

Breast cancer remains one of the leading causes of cancer mortality in the US. Elevated cholesterol is a major risk factor for breast cancer onset and recurrence, while cholesterol-lowering drugs, such as statins, are associated with a good prognosis. Previous work in murine models showed that cholesterol increases breast cancer metastasis, and the pro-metastatic effects of cholesterol were due to its primary metabolite, 27-hydroxycholesterol (27HC). In our prior work, myeloid cells were found to be required for the pro-metastatic effects of 27HC, but their precise contribution remains unclear. Here we report that 27HC impairs T cell expansion and cytotoxic function through its actions on myeloid cells, including macrophages, in a Liver X receptor (LXR) dependent manner. Many oxysterols and LXR ligands had similar effects on T cell expansion. Moreover, their ability to induce the LXR target gene ABCA1 was associated with their effectiveness in impairing T cell expansion. Induction of T cell apoptosis was likely one mediator of this impairment. Interestingly, the enzyme responsible for the synthesis of 27HC, CYP27A1, is highly expressed in myeloid cells, suggesting that 27HC may have important autocrine or paracrine functions in these cells, a hypothesis supported by our finding that breast cancer metastasis was reduced in mice with a myeloid specific knockout of CYP27A1. Importantly, pharmacologic inhibition of CYP27A1 reduced metastatic growth and improved the efficacy of checkpoint inhibitor, anti -PD-L1. Taken together, our work suggests that targeting the CYP27A1 axis in myeloid cells may present therapeutic benefits and improve the response rate to immune therapies in breast cancer. • The cholesterol metabolite, 27-Hydroxycholesterol (27HC), works on myeloid cells to suppress T cell activity. • 27HC-LXR activity mediates myeloid cell-driven immune suppression. • Myeloid cell-driven T cell inhibition likely results from accelerated T cell apoptosis. • Pharmacologic inhibition of 27HC synthesis enhances immune check-point inhibition. • The immune suppression is likely a dominant mechanism by which 27HC promotes breast cancer progression. [ABSTRACT FROM AUTHOR]

In light of PRP's increasing popularity in veterinary practice, this study aimed to compare three manual methods to prepare and cool equine PRP. The blood of 18 clinically healthy mares was collected via venipuncture in a blood transfusion bag (method 1), blood tubes (method 2), and a syringe (method 3). In method 1, samples were double centrifuged; method 2 involved one centrifugation, and in method 3 the syringe was kept in an upright position to sediment for 4 h. After processing with three methods, PRP and platelet-poor plasma (PPP) were extracted and assessed for red (RBC) and white blood cell counts (WBC), platelet counts, and viability. In a subset of mares ( n = 6), samples were processed with the three methods, and PRP was evaluated at 6 and 24 h postcooling at 5 °C. Method 1 resulted in the highest and method 3 in the lowest platelet concentration ( p < 0.05), and the latter also had greater contamination with WBC than the others ( p < 0.001). Platelet viability was similar across treatments ( p > 0.05). Cooling for 24 h did not affect platelet counts in all methods ( p > 0.05); however, platelet viability was reduced after cooling PRP produced by method 3 ( p = 0.04), and agglutination increased over time in all methods ( p < 0.001). The three methods increased (1.8-5.6-fold) platelet concentration in PRP compared to whole blood without compromising platelet viability. In conclusion, all three methods concentrated platelets and while cooling affected their viability. It remains unknown whether the different methods and cooling would affect PRP's clinical efficacy.

Fungal infections in CD4 + T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8 + T cell responses and immunity to inactivated vaccine in the absence of CD4 + T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8 + T cells in response to inactivated fungal vaccination in a mouse model of CD4 + T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-γ) and type 17 (IL-17A) CD8 + T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb -/- mice. Augmented CD8 + T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and RORγt. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8 + T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8 + T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Levels of the anaphylatoxin C3a are increased in patients with asthma compared with those in nonasthmatics and increase further still during asthma exacerbations. However, the role of C3a during sensitization to allergen is poorly understood. Sensitization to fungal allergens, such as Aspergillus fumigatus, is a strong risk factor for the development of asthma. Exposure to chitin, a structural polysaccharide of the fungal cell wall, induces innate allergic inflammation and may promote sensitization to fungal allergens. Here, we found that coincubation of chitin with serum or intratracheal administration of chitin in mice resulted in the generation of C3a. We established a model of chitin-dependent sensitization to soluble Aspergillus antigens to test the contribution of complement to these events. C3(-/-) and C3aR(-/-) mice were protected from chitin-dependent sensitization to Aspergillus and had reduced lung eosinophilia and type 2 cytokines and serum IgE. In contrast, complement-deficient mice were not protected against chitin-induced innate allergic inflammation. In sensitized mice, plasmacytoid dendritic cells from complement-deficient animals acquired a tolerogenic profile associated with enhanced regulatory T cell responses and suppressed Th2 and Th17 responses specific for Aspergillus. Thus, chitin induces the generation of C3a in the lung, and chitin-dependent allergic sensitization to Aspergillus requires C3aR signaling, which suppresses regulatory dendritic cells and T cells and induces allergy-promoting T cells.

The E3 ubiquitin ligase Cbl-b is a negative regulator of TCR signaling that: 1) sets the activation threshold for T cells; 2) is induced in anergic T cells; and 3) protects against autoimmunity. However, the role of Cbl-b in regulating CD8 T cell activation and functions during physiological T cell responses has not been systematically examined. Using the lymphocytic choriomeningitis virus infection model, we show that Cbl-b deficiency did not significantly affect the clonal expansion of virus-specific CD8 T cells. However, Cbl-b deficiency not only increased the steady-state cell surface expression levels of TCR and CD8 but also reduced Ag-induced down-modulation of cell surface TCR expression by effector CD8 T cells. Diminished Ag-stimulated TCR down-modulation and sustained Ag receptor signaling induced by Cbl-b deficiency markedly augmented IFN-gamma production, which is known to require substantial TCR occupancy. By contrast, Cbl-b deficiency minimally affected cell-mediated cytotoxicity, which requires limited engagement of TCRs. Surprisingly, despite elevated expression of CD8 and reduced Ag-induced TCR down-modulation, the functional avidity of Cbl-b-deficient effector CD8 T cells was comparable to that of wild-type effectors. Collectively, these data not only show that Cbl-b-imposed constraint on TCR signaling has differential effects on various facets of CD8 T cell response but also suggest that Cbl-b might mitigate tissue injury induced by the overproduction of IFN-gamma by CD8 T cells. These findings have implications in the development of therapies to bolster CD8 T cell function during viral infections or suppress T cell-mediated immunopathology.