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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 [...]

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]

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.)

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.