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1.
J Leukoc Biol ; 115(6): 1118-1130, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38271280

ABSTRACT

Nontuberculous mycobacteria (NTM) are emerging opportunistic pathogens causing pulmonary infection to fatal disseminated disease. NTM infections are steadily increasing in children and adults, and immune-compromised individuals are at a greater risk of fatal infections. The NTM disease's adverse pathology and resistance to antibiotics have further worsened the therapeutic measures. Innate immune regulators are potential targets for therapeutics to NTM, especially in a T cell-suppressed population, and many ubiquitin ligases modulate pathogenesis and innate immunity during infections, including mycobacterial infections. Here, we investigated the role of an E3 ubiquitin ligase, Casitas B-lineage lymphoma proto-oncogene B (CBLB), in immunocompromised mouse models of NTM infection. We found that CBLB is essential to prevent bacterial growth and dissemination. Cblb deficiency debilitated natural killer cells, inflammatory monocytes, and macrophages in vivo. However, Cblb deficiency in macrophages did not wane its ability to inhibit bacterial growth or production of reactive oxygen species or interferon γ production by natural killer cells in vitro. CBLB restricted NTM growth and dissemination by promoting early granuloma formation in vivo. Our study shows that CBLB bolsters innate immune responses and helps prevent the dissemination of NTM during compromised T cell immunity.


Subject(s)
Immunity, Innate , Mycobacterium Infections, Nontuberculous , Proto-Oncogene Proteins c-cbl , Animals , Proto-Oncogene Proteins c-cbl/deficiency , Proto-Oncogene Proteins c-cbl/metabolism , Proto-Oncogene Proteins c-cbl/genetics , Mice , Mycobacterium Infections, Nontuberculous/immunology , Mycobacterium Infections, Nontuberculous/microbiology , Killer Cells, Natural/immunology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Nontuberculous Mycobacteria/immunology , Macrophages/immunology , Macrophages/microbiology , Macrophages/metabolism , Mice, Inbred C57BL , Mice, Knockout , Granuloma/immunology , Granuloma/microbiology , Granuloma/pathology
3.
Cell Rep ; 41(4): 111543, 2022 10 25.
Article in English | MEDLINE | ID: mdl-36288707

ABSTRACT

GM-CSF co-expressing T17 cells instigate pathologic inflammation during autoimmune disorders, but their function in immunity to infections is unclear. Here, we demonstrate the role of GM-CSF+Tc17 cells for vaccine immunity against lethal fungal pneumonia and the cytokine requirements for their induction and memory homeostasis. Vaccine-induced GM-CSF+ Tc17 cells are necessary to bolster pulmonary fungal immunity without inflating pathology. Although GM-CSF expressing Tc17 cells preferentially elevate during the memory phase, their phenotypic attributes strongly suggest they are more like Tc17 cells than IFNγ-producing Tc1 cells. IL-1 and IL-23, but not GM-CSF, are necessary to elicit GM-CSF+ Tc17 cells following vaccination. IL-23 is dispensable for memory Tc17 and GM-CSF+ Tc17 cell maintenance, but recall responses of effector or memory Tc17 cells in the lung require it. Our study reveals the beneficial, nonpathological role of GM-CSF+ Tc17 cells during fungal vaccine immunity.


Subject(s)
Pneumonia , Vaccines , Animals , Mice , CD8-Positive T-Lymphocytes , Mice, Inbred C57BL , Pneumonia/microbiology , Interleukin-23 , Interleukin-1
4.
Front Immunol ; 13: 905867, 2022.
Article in English | MEDLINE | ID: mdl-36177012

ABSTRACT

In recent years, fungal vaccine research emanated significant findings in the field of antifungal T-cell immunity. The generation of effector T cells is essential to combat many mucosal and systemic fungal infections. The development of antifungal memory T cells is integral for controlling or preventing fungal infections, and understanding the factors, regulators, and modifiers that dictate the generation of such T cells is necessary. Despite the deficiency in the clear understanding of antifungal memory T-cell longevity and attributes, in this review, we will compile some of the existing literature on antifungal T-cell immunity in the context of memory T-cell development against fungal infections.


Subject(s)
Fungal Vaccines , Mycoses , Antifungal Agents , CD8-Positive T-Lymphocytes , Humans , Immunologic Memory
5.
Viruses ; 14(5)2022 05 18.
Article in English | MEDLINE | ID: mdl-35632822

ABSTRACT

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.


Subject(s)
Gastrointestinal Microbiome , Porcine Reproductive and Respiratory Syndrome , Porcine respiratory and reproductive syndrome virus , Viral Vaccines , Animals , CD8-Positive T-Lymphocytes , Porcine Reproductive and Respiratory Syndrome/prevention & control , Swine , Vaccines, Attenuated , Vaccines, Inactivated
6.
Animals (Basel) ; 11(6)2021 May 21.
Article in English | MEDLINE | ID: mdl-34063777

ABSTRACT

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.

7.
Am J Pathol ; 191(1): 108-130, 2021 01.
Article in English | MEDLINE | ID: mdl-33069717

ABSTRACT

Pulmonary mycoses are difficult to treat and detrimental to patients. Fungal infections modulate the lung immune response, induce goblet cell hyperplasia and metaplasia, and mucus hypersecretion in the airways. Excessive mucus clogs small airways and reduces pulmonary function by decreasing oxygen exchange, leading to respiratory distress. The forkhead box protein A2 (FOXA2) is a transcription factor that regulates mucus homeostasis in the airways. However, little is known whether pulmonary mycosis modulates FOXA2 function. Herein, we investigated whether Blastomyces dermatitidis and Histoplasma capsulatum-infected canine and feline lungs and airway epithelial cells could serve as higher animal models to examine the relationships between fungal pneumonia and FOXA2-regulated airway mucus homeostasis. The results indicate that fungal infection down-regulated FOXA2 expression in airway epithelial cells, with concomitant overexpression of mucin 5AC (MUC5AC) and mucin 5B (MUC5B) mucins. Mechanistic studies reveal that B. dermatitidis infection, as well as ß-glucan exposure, activated the Dectin-1-SYK-epidermal growth factor receptor-AKT/extracellular signal-regulated kinase 1/2 signaling pathway that inhibits the expression of FOXA2, resulting in overexpression of MUC5AC and MUC5B in canine airway cells. Further understanding of the role of FOXA2 in mucus hypersecretion may lead to novel therapeutics against excessive mucus in both human and veterinary patients with pulmonary mycosis.


Subject(s)
Blastomycosis/metabolism , Histoplasmosis/metabolism , Lung Diseases, Fungal/metabolism , Mucus/metabolism , Signal Transduction/physiology , Animals , Blastomycosis/pathology , Cats , Disease Models, Animal , Dogs , ErbB Receptors/metabolism , Hepatocyte Nuclear Factor 3-beta/metabolism , Histoplasma , Histoplasmosis/pathology , Lung Diseases, Fungal/pathology , MAP Kinase Signaling System/physiology , Proto-Oncogene Proteins c-akt/metabolism , Syk Kinase/metabolism
8.
Cancer Lett ; 493: 266-283, 2020 11 28.
Article in English | MEDLINE | ID: mdl-32861706

ABSTRACT

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.


Subject(s)
Breast Neoplasms/pathology , Cholestanetriol 26-Monooxygenase/genetics , Hydroxycholesterols/adverse effects , Myeloid Cells/metabolism , T-Lymphocytes/metabolism , ATP Binding Cassette Transporter 1/metabolism , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cholestanetriol 26-Monooxygenase/metabolism , Female , Gene Knockout Techniques , Humans , Liver X Receptors/metabolism , Mice , Myeloid Cells/drug effects , Neoplasm Transplantation , T-Lymphocytes/drug effects
9.
J Immunol ; 201(6): 1717-1726, 2018 09 15.
Article in English | MEDLINE | ID: mdl-30054317

ABSTRACT

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.


Subject(s)
Adaptor Proteins, Signal Transducing/immunology , CD8-Positive T-Lymphocytes/immunology , Fungal Vaccines/immunology , Immunity, Cellular , Lung Diseases, Fungal/immunology , Pneumonia/immunology , Proto-Oncogene Proteins c-cbl/immunology , Adaptor Proteins, Signal Transducing/genetics , Animals , CD8-Positive T-Lymphocytes/pathology , Fungal Vaccines/pharmacology , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-17/genetics , Interleukin-17/immunology , Lung Diseases, Fungal/genetics , Lung Diseases, Fungal/pathology , Lung Diseases, Fungal/prevention & control , Mice , Mice, Knockout , Pneumonia/genetics , Pneumonia/pathology , Pneumonia/prevention & control , Proto-Oncogene Proteins c-cbl/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/immunology , Vaccines, Inactivated/immunology , Vaccines, Inactivated/pharmacology
10.
PLoS Pathog ; 13(5): e1006356, 2017 May.
Article in English | MEDLINE | ID: mdl-28542595

ABSTRACT

Our understanding of persistence and plasticity of IL-17A+ memory T cells is clouded by conflicting results in models analyzing T helper 17 cells. We studied memory IL-17A+ CD8+ T-cell (Tc17) homeostasis, persistence and plasticity during fungal vaccine immunity. We report that vaccine-induced memory Tc17 cells persist with high fidelity to the type 17 phenotype. Tc17 cells persisted durably for a year as functional IL-17A+ memory cells without converting to IFNγ+ (Tc1) cells, although they produced multiple type I cytokines in the absence of residual vaccine antigen. Memory Tc17 cells were canonical CD8+ T cells with phenotypic features distinct from Tc1 cells, and were Ror(γ)thi, TCF-1hi, T-betlo and EOMESlo. In investigating the bases of Tc17 persistence, we observed that memory Tc17 cells had much higher levels of basal homeostatic proliferation than did Tc1 cells. Conversely, memory Tc17 cells displayed lower levels of anti-apoptotic molecules Bcl-2 and Bcl-xL than Tc1 cells, yet were resistant to apoptosis. Tc1 cells required Bcl-2 for their survival, but Bcl-2 was dispensable for the maintenance of Tc17 cells. Tc17 and Tc1 cells displayed different requirements for HIF-1α during effector differentiation and sustenance and memory persistence. Thus, antifungal vaccination induces durable and stable memory Tc17 cells with distinct requirements for long-term persistence that distinguish them from memory Tc1 cells.


Subject(s)
Blastomyces/immunology , Blastomycosis/immunology , Fungal Vaccines/immunology , Immunologic Memory , Interferon-gamma/immunology , Th17 Cells/immunology , Animals , Blastomycosis/microbiology , Blastomycosis/physiopathology , Blastomycosis/prevention & control , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation , Humans , Interleukin-17/immunology , Mice , Mice, Inbred C57BL , Th17 Cells/cytology
11.
PLoS Pathog ; 11(9): e1005161, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26367276

ABSTRACT

Fungal infections have skyrocketed in immune-compromised patients lacking CD4+ T cells, underscoring the need for vaccine prevention. An understanding of the elements that promote vaccine immunity in this setting is essential. We previously demonstrated that vaccine-induced IL-17A+ CD8+ T cells (Tc17) are required for resistance against lethal fungal pneumonia in CD4+ T cell-deficient hosts, whereas the individual type I cytokines IFN-γ, TNF-α and GM-CSF, are dispensable. Here, we report that T cell-intrinsic MyD88 signals are crucial for these Tc17 cell responses and vaccine immunity against lethal fungal pneumonia in mice. In contrast, IFN-γ+ CD8+ cell (Tc1) responses are largely normal in the absence of intrinsic MyD88 signaling in CD8+ T cells. The poor accumulation of MyD88-deficient Tc17 cells was not linked to an early onset of contraction, nor to accelerated cell death or diminished expression of anti-apoptotic molecules Bcl-2 or Bcl-xL. Instead, intrinsic MyD88 was required to sustain the proliferation of Tc17 cells through the activation of mTOR via Akt1. Moreover, intrinsic IL-1R and TLR2, but not IL-18R, were required for MyD88 dependent Tc17 responses. Our data identify unappreciated targets for augmenting adaptive immunity against fungi. Our findings have implications for designing fungal vaccines and immune-based therapies in immune-compromised patients.


Subject(s)
Blastomyces/immunology , Blastomycosis/prevention & control , Fungal Vaccines/therapeutic use , Immunologic Memory , Pneumonia/prevention & control , T-Lymphocytes, Cytotoxic/immunology , Th17 Cells/immunology , Animals , Blastomyces/physiology , Blastomycosis/immunology , Blastomycosis/metabolism , Blastomycosis/microbiology , Cell Proliferation , Cells, Cultured , Lymphocyte Depletion , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myeloid Differentiation Factor 88/metabolism , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/microbiology , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Interleukin-1 Type I/metabolism , Signal Transduction , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/microbiology , T-Lymphocytes, Cytotoxic/pathology , TOR Serine-Threonine Kinases/metabolism , Th17 Cells/metabolism , Th17 Cells/microbiology , Th17 Cells/pathology , Toll-Like Receptor 2/metabolism
13.
PLoS Pathog ; 9(7): e1003464, 2013.
Article in English | MEDLINE | ID: mdl-23853587

ABSTRACT

Blastomyces adhesin-1 (BAD-1) is a 120-kD surface protein on B. dermatitidis yeast. We show here that BAD-1 contains 41 tandem repeats and that deleting even half of them impairs fungal pathogenicity. According to NMR, the repeats form tightly folded 17-amino acid loops constrained by a disulfide bond linking conserved cysteines. Each loop contains a highly conserved WxxWxxW motif found in thrombospondin-1 (TSP-1) type 1 heparin-binding repeats. BAD-1 binds heparin specifically and saturably, and is competitively inhibited by soluble heparin, but not related glycosaminoglycans. According to SPR analysis, the affinity of BAD-1 for heparin is 33 nM±14 nM. Putative heparin-binding motifs are found both at the N-terminus and within each tandem repeat loop. Like TSP-1, BAD-1 blocks activation of T cells in a manner requiring the heparan sulfate-modified surface molecule CD47, and impairs effector functions. The tandem repeats of BAD-1 thus confer pathogenicity, harbor motifs that bind heparin, and suppress T-cell activation via a CD47-dependent mechanism, mimicking mammalian TSP-1.


Subject(s)
Antigens, Fungal/metabolism , Antigens, Surface/metabolism , Blastomyces/immunology , Fungal Proteins/metabolism , Heparin/metabolism , Lymphocyte Activation , T-Lymphocytes/immunology , Animals , Antigens, Fungal/chemistry , Antigens, Fungal/genetics , Antigens, Surface/chemistry , Antigens, Surface/genetics , Blastomyces/chemistry , Blastomyces/metabolism , Blastomyces/pathogenicity , Blastomycosis/immunology , Blastomycosis/metabolism , Blastomycosis/microbiology , CD47 Antigen/chemistry , CD47 Antigen/genetics , CD47 Antigen/metabolism , Cells, Cultured , Fungal Proteins/chemistry , Fungal Proteins/genetics , Humans , Jurkat Cells , Male , Mice, Inbred BALB C , Mice, Transgenic , Mutant Proteins/chemistry , Mutant Proteins/metabolism , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Tandem Repeat Sequences , Thrombospondin 1/chemistry , Thrombospondin 1/metabolism , Virulence
14.
mBio ; 4(2)2013 Apr 02.
Article in English | MEDLINE | ID: mdl-23549917

ABSTRACT

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.


Subject(s)
Aspergillus fumigatus/immunology , Chitin/immunology , Complement C3/immunology , Receptors, Complement/immunology , Animals , Aspergillosis, Allergic Bronchopulmonary/immunology , Aspergillosis, Allergic Bronchopulmonary/pathology , Complement C3/genetics , Dendritic Cells/immunology , Mice , Mice, Knockout , Receptors, Complement/genetics , T-Lymphocytes/immunology
15.
PLoS Pathog ; 8(7): e1002771, 2012.
Article in English | MEDLINE | ID: mdl-22829762

ABSTRACT

Vaccines may help reduce the growing incidence of fungal infections in immune-suppressed patients. We have found that, even in the absence of CD4(+) T-cell help, vaccine-induced CD8(+) T cells persist and confer resistance against Blastomyces dermatitidis and Histoplasma capsulatum. Type 1 cytokines contribute to that resistance, but they also are dispensable. Although the role of T helper 17 cells in immunity to fungi is debated, IL-17 producing CD8(+) T cells (Tc17 cells) have not been investigated. Here, we show that Tc17 cells are indispensable in antifungal vaccine immunity in hosts lacking CD4(+) T cells. Tc17 cells are induced upon vaccination, recruited to the lung on pulmonary infection, and act non-redundantly in mediating protection in a manner that requires neutrophils. Tc17 cells did not influence type I immunity, nor did the lack of IL-12 signaling augment Tc17 cells, indicating a distinct lineage and function. IL-6 was required for Tc17 differentiation and immunity, but IL-1R1 and Dectin-1 signaling was unexpectedly dispensable. Tc17 cells expressed surface CXCR3 and CCR6, but only the latter was essential in recruitment to the lung. Although IL-17 producing T cells are believed to be short-lived, effector Tc17 cells expressed low levels of KLRG1 and high levels of the transcription factor TCF-1, predicting their long-term survival and stem-cell like behavior. Our work has implications for designing vaccines against fungal infections in immune suppressed patients.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Fungal Vaccines/immunology , Lung Diseases, Fungal/immunology , Pneumonia/immunology , Th17 Cells/immunology , Animals , Blastomyces/immunology , Blastomyces/pathogenicity , Blastomycosis/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Hepatocyte Nuclear Factor 1-alpha , Histoplasma/immunology , Histoplasma/pathogenicity , Histoplasmosis/immunology , Immunocompromised Host , Immunologic Deficiency Syndromes/immunology , Immunologic Memory/immunology , Interleukin-12/biosynthesis , Interleukin-17/biosynthesis , Interleukin-17/immunology , Interleukin-6/biosynthesis , Interleukin-6/immunology , Lectins, C-Type/metabolism , Lung/immunology , Lung/microbiology , Lung Diseases, Fungal/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/immunology , Pneumonia/microbiology , Receptors, CCR6/biosynthesis , Receptors, CCR6/metabolism , Receptors, CXCR3/biosynthesis , Receptors, Immunologic/biosynthesis , Signal Transduction , T Cell Transcription Factor 1/biosynthesis
16.
J Clin Invest ; 122(3): 987-99, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22354169

ABSTRACT

Individuals who are immunocompromised, including AIDS patients with few CD4(+) 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 CD4(+) T cells play a dominant role in resistance to many pathogenic fungal infections, we have previously shown that vaccination can induce protective antifungal CD8(+) T cell immunity in the absence of CD4(+) T cells. However, it has not been determined whether vaccine-induced antifungal CD8(+) T cell memory can be maintained in the absence of CD4(+) T cell help. Here, we have shown in a mouse model of vaccination against blastomycosis that antifungal memory CD8(+) T cells are maintained in the absence of CD4(+) 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 CD8(+) T cells, we found that such cells were maintained for at least 5 months upon transfer into naive mice lacking both CD4(+) T cells and persistent fungal antigen. Additionally, fungal vaccination induced a profile of transcription factors functionally linked with persistent memory in CD8(+) T cells. Thus, unlike bacteria and viruses, fungi elicit long-term CD8(+) T cell memory that is maintained without CD4(+) T cell help or persistent antigen. This has implications for the development of novel antifungal vaccine strategies effective in immunocompromised patients.


Subject(s)
Antigens/chemistry , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Adoptive Transfer , Alleles , Animals , Antifungal Agents/pharmacology , Cancer Vaccines , Cytokines/metabolism , Epitopes/chemistry , Flow Cytometry/methods , Immune System , Immunologic Memory , Mice , Mice, Inbred C57BL , Risk , Transcription Factors/metabolism
17.
Blood ; 117(19): 5123-32, 2011 May 12.
Article in English | MEDLINE | ID: mdl-21436066

ABSTRACT

Viral persistence during chronic viral infections is associated with a progressive loss of T-cell effector function called functional exhaustion. There is therefore a need to develop immunotherapies to remediate the functional deficits of T cells during these infections. We investigated the immunotherapeutic effects of IL-7 during chronic lymphocytic choriomeningitis virus infection in mice. Our results showed that the effects of IL-7 on T cells depend on the viral load, timing, and duration of treatment during the course of the infection. We document that the effectiveness of IL-7 was constrained by high viral load early in the infection, but treatment for at least 3 weeks during declining viral titers mitigated the programmed contraction of CD8 T cells, markedly enhanced the number of high-quality polyfunctional virus-specific CD8 T cells with a nonexhausted phenotype, and accelerated viral control. Mechanistically, the enhancement of CD8 T-cell responses by IL-7 was associated with increased proliferation and induction of Bcl-2, but not with altered levels of PD-1 or Cbl-b. In summary, our results strongly suggest that IL-7 therapy is a potential strategy to bolster the quality and quantity of T-cell responses in patients with chronic viral infections.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , Immunologic Factors/therapeutic use , Interleukin-7/therapeutic use , Lymphocytic Choriomeningitis/drug therapy , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Separation , Chronic Disease , Flow Cytometry , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Mice , Mice, Inbred C57BL
18.
J Clin Invest ; 118(3): 1027-39, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18246202

ABSTRACT

IL-7 is integral to the generation and maintenance of CD8(+) T cell memory, and insufficient IL-7 is believed to limit survival and the persistence of memory CD8(+) T cells. Here, we show that during the mouse T cell response to lymphocytic choriomeningitis virus, IL-7 enhanced the number of memory CD8(+) 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(+) memory T cell proliferation and function. Qualitatively, CD8(+) 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(+) T cells, but the effects were transient. IL-7 therapy during contraction of the secondary CD8(+) T cell response also expanded the pool of memory CD8(+) T cells. Collectively, our studies show differential effects of IL-7 on memory CD8(+) T cell homeostasis and underscore the importance of the timing of IL-7 therapy to effectively improve CD8(+) 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(+) T cell memory.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/drug effects , Interleukin-7/pharmacology , Animals , Homeostasis , Interleukin-7/therapeutic use , Lymphocyte Activation/drug effects , Lymphocytic Choriomeningitis/drug therapy , Lymphocytic Choriomeningitis/immunology , Mice , Mice, Inbred C57BL , Time Factors , Tumor Necrosis Factor-alpha/biosynthesis , Vaccines, DNA/immunology , Viral Vaccines/immunology
19.
J Immunol ; 179(11): 7233-43, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-18025165

ABSTRACT

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.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Antigens, Viral/immunology , CD8-Positive T-Lymphocytes/immunology , Interferon-gamma/biosynthesis , Lymphocytic choriomeningitis virus/immunology , Proto-Oncogene Proteins c-cbl/physiology , Receptors, Antigen, T-Cell/metabolism , Adaptor Proteins, Signal Transducing/biosynthesis , Adaptor Proteins, Signal Transducing/deficiency , Animals , Antigen Presentation/immunology , CD8 Antigens/biosynthesis , CD8 Antigens/immunology , CD8-Positive T-Lymphocytes/virology , Disease Models, Animal , Down-Regulation/immunology , Epitopes, T-Lymphocyte/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Peptides/pharmacology , Proto-Oncogene Proteins c-cbl/biosynthesis , Proto-Oncogene Proteins c-cbl/deficiency , Receptors, Antigen, T-Cell/biosynthesis , Spleen/cytology , Spleen/drug effects , Spleen/immunology
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