MycobacteriumulceransTriggers T-Cell Immunity followed by Local and Regional but Not Systemic Immunosuppression

ABSTRACTBuruli ulcer is a neglected infectious disease caused byMycobacterium ulceransand is characterized by necrotic cutaneous lesions induced by the exotoxin mycolactone. Despite evidence of Th1-mediated protective immunity,M. ulceransinfection has been associated with systemic immunosuppression. We show that early during mouse infection with either mycolactone-positive or negative strains, pathogen-specific gamma interferon (IFN-γ)-producing T cells developed in the draining lymph node (DLN). CD4+cells migrated to the infection foci, but progressive infection with virulentM. ulceransled to the local depletion of recruited cells. Moreover, dissemination of virulentM. ulceransto the DLN was accompanied by extensive DLN apoptotic cytopathology, leading to depletion of CD4+T cells and abrogation of IFN-γ expression. Advanced footpad infection with virulentM. ulceransdid not induce increased susceptibility to systemic coinfection byListeria monocytogenes. These results show that infection withM. ulceransefficiently triggers a mycobacterium-specific T-cell response in the DLN and that progression of infection with highly virulentM. ulceransleads to a local and regional suppression of that immune response, but without induction of systemic immunosuppression. These results suggest that prophylactic and/or therapeutic interventions to prevent dissemination ofM. ulceransto DLN during the early phase of infection would contribute for the maintenance of protective immunity and disease control.

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T Cell Immunity Evaluation and Immunodominant Epitope T Cell Receptor Identification of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Glycoprotein in COVID-19 Convalescent Patients

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.696662 ◽

2021 ◽

Vol 9 ◽

Author(s):

Luo Li ◽

Qian Chen ◽

Xiaojian Han ◽

Meiying Shen ◽

Chao Hu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Severe Acute Respiratory Syndrome ◽

Vaccine Development ◽

Cell Receptor ◽

T Cell Response ◽

Cell Immunity ◽

Ifn Γ

A better understanding of the role of T cells in the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is helpful not only for vaccine development but also for the treatment of COVID-19 patients. In this study, we determined the existence of SARS-CoV-2-specific T cells in the blood of COVID-19 convalescents. Meanwhile, the specific T cell response in the non-RBD region was stronger than in the RBD region. We also found that SARS-CoV-2 S-specific reactive CD4+ T cells exhibited higher frequency than CD8+ T cells in recovered COVID-19 patients, with greater number of corresponding epitopes presented. Importantly, we isolated the SARS-CoV-2-specific CD4+ T cell receptors (TCRs) and inserted the TCRs into allogenic CD4+ T cells. These TCR-T cells can be activated by SARS-CoV-2 spike peptide and produce IFN-γ in vitro. These results might provide valuable information for the development of vaccines and new therapies against COVID-19.

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Combination of a Sindbis-SARS-CoV-2 Spike Vaccine and αOX40 Antibody Elicits Protective Immunity Against SARS-CoV-2 Induced Disease and Potentiates Long-Term SARS-CoV-2-Specific Humoral and T-Cell Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.719077 ◽

2021 ◽

Vol 12 ◽

Author(s):

Antonella Scaglione ◽

Silvana Opp ◽

Alicia Hurtado ◽

Ziyan Lin ◽

Christine Pampeno ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Protective Immunity ◽

T Cell Response ◽

Spike Protein ◽

Effector Memory ◽

Vaccine Platform ◽

Cell Immunity ◽

Vaccine Approach

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world’s population at record speeds. However, there is still a demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (αOX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T-cell response in mice. Protein binding, immunohistochemical, and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles, and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response, which can be used as a new candidate to combat SARS-CoV-2. Given the T-cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

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Simvastatin Reduces Protection and Intestinal T Cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs

Pathogens ◽

10.3390/pathogens10070829 ◽

2021 ◽

Vol 10 (7) ◽

pp. 829

Author(s):

Jacob Kocher ◽

Tammy Bui Castellucci ◽

Ke Wen ◽

Guohua Li ◽

Xingdong Yang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Responses ◽

T Cell Response ◽

Post Inoculation ◽

Cell Responses ◽

Monophosphoryl Lipid A ◽

Cell Immunity ◽

Ifn Γ

Noroviruses (NoVs) are a leading cause of acute gastroenteritis worldwide. P particles are a potential vaccine candidate against NoV. Simvastatin is a cholesterol-reducing drug that is known to increase NoV infectivity. In this study, we examined simvastatin’s effects on P particle-induced protective efficacy and T-cell immunogenicity using the gnotobiotic pig model of human NoV infection and diarrhea. Pigs were intranasally inoculated with three doses (100 µg/dose) of GII.4/VA387-derived P particles together with monophosphoryl lipid A and chitosan adjuvants. Simvastatin-fed pigs received 8 mg/day orally for 11 days prior to challenge. A subset of pigs was orally challenged with 10 ID50 of a NoV GII.4/2006b variant at post-inoculation day (PID) 28 and monitored for 7 days post-challenge. Intestinal and systemic T cell responses were determined pre- and postchallenge. Simvastatin abolished the P particle’s protection and significantly increased diarrhea severity after NoV infection. Simvastatin decreased proliferation of virus-specific and non-specific CD8 T cells in duodenum and virus-specific CD4 and CD8 T cells in spleen and significantly reduced numbers of intestinal mononuclear cells in vaccinated pigs. Furthermore, simvastatin significantly decreased numbers of duodenal CD4+IFN-γ+, CD8+IFN-γ+ and regulatory T cells and total duodenal activated CD4+ and CD8+ T cells in vaccinated pigs pre-challenge at PID 28. Following challenge, simvastatin prevented the IFN-γ+ T cell response in spleen of vaccinated pigs. These results indicate that simvastatin abolished P particle vaccine-induced partial protection through, at least in part, impairing T cell immunity. The findings have specific implications for the development of preventive and therapeutic strategies against NoV gastroenteritis, especially for the elderly population who takes statin-type drugs.

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Proapoptotic Bcl-2 Family Member Bim Promotes Persistent Infection and Limits Protective Immunity

Infection and Immunity ◽

10.1128/iai.01093-06 ◽

2007 ◽

Vol 76 (3) ◽

pp. 1179-1185 ◽

Cited By ~ 19

Author(s):

Stacie Reckling ◽

Senad Divanovic ◽

Christopher L. Karp ◽

Sara Wojciechowski ◽

Yasmine Belkaid ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Family Member ◽

Persistent Infection ◽

Protective Immunity ◽

Leishmania Major ◽

Interleukin 10 ◽

Effector T Cells ◽

T Cell Response ◽

Ifn Γ

ABSTRACT Following the peak of the T-cell response, most of the activated effector T cells die by apoptosis driven by the proapoptotic Bcl-2 family member Bim (Bcl-2-interacting mediator of death). Whether the absence of Bim-mediated T-cell apoptosis can affect protective immunity remains unclear. Here, we used a mouse model of Leishmania major infection, in which parasite persistence and protective immunity are controlled by an equilibrium reached between parasite-specific gamma interferon (IFN-γ)-producing effector T cells and interleukin-10 (IL-10)-producing CD4+ CD25+ T regulatory cells. To further understand the role of Bim-mediated apoptosis in persistent infection and protective immunity, we infected Bim −/− mice with L. major. We found that the initial parasite growth and lesion development were similar in Bim −/− and wild-type mice after primary L. major infection. However, at later times after infection, Bim −/− mice had significantly increased L. major-specific CD4+ T-cell responses and were resistant to persistent infection. Interestingly, despite their resistance to primary L. major infection, Bim −/− mice displayed significantly enhanced protection against challenge with L. major. Increased resistance to challenge in Bim −/− mice was associated with a significant increase in the number of L. major-specific IFN-γ-producing CD4+ T cells and a lack of IL-10 production at the challenge site. Taken together, these data suggest that Bim limits protective immunity and that the absence of Bim allows the host to bypass antigen persistence for maintenance of immunity against reinfection.

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CD8+-T-Cell Immunity against Toxoplasma gondii Can Be Induced but Not Maintained in Mice Lacking Conventional CD4+ T Cells

Infection and Immunity ◽

10.1128/iai.70.2.434-443.2002 ◽

2002 ◽

Vol 70 (2) ◽

pp. 434-443 ◽

Cited By ~ 65

Author(s):

Lori Casciotti ◽

Kenneth H. Ely ◽

Martha E. Williams ◽

Imtiaz A. Khan

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Toxoplasma Gondii ◽

Cell Response ◽

T Cell Response ◽

T Cell Immunity ◽

Cell Immune Response ◽

Cell Immunity ◽

Ifn Γ

ABSTRACT T-cell immunity is critical for survival of hosts infected with Toxoplasma gondii. Among the cells in the T-cell population, CD8+ T cells are considered the major effector cells against this parasite. It is believed that CD4+ T cells may be crucial for induction of the CD8+-T-cell response against T. gondii. In the present study, CD4−/− mice were used to evaluate the role of conventional CD4+ T cells in the immune response against T. gondii infection. CD4−/− mice infected with T. gondii exhibited lower gamma interferon (IFN-γ) messages in the majority of their tissues. As a result, mortality due to a hyperinflammatory response was prevented in these animals. Interestingly, T. gondii infection induced a normal antigen-specific CD8+-T-cell immune response in CD4−/− mice. No difference in generation of precursor cytotoxic T lymphocytes (pCTL) or in IFN-γ production by the CD8+-T-cell populations from the knockout and wild-type animals was observed. However, the mutant mice were not able to sustain CD8+-T-cell immunity. At 180 days after infection, the CD8+-T-cell response in the knockout mice was depressed, as determined by pCTL and IFN-γ assays. Loss of CD8+-T-cell immunity at this time was confirmed by adoptive transfer experiments. Purified CD8+ T cells from CD4−/− donors that had been immunized 180 days earlier failed to protect the recipient mice against a lethal infection. Our study demonstrated that although CD8+-T-cell immunity can be induced in the absence of conventional CD4+ T cells, it cannot be maintained without such cells.

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Immunological studies of T-cell receptors. I. Specifically induced resistance to graft-versus-host disease in rats mediated by host T-cell immunity to alloreactive parental T cells.

Journal of Experimental Medicine ◽

10.1084/jem.148.1.103 ◽

1978 ◽

Vol 148 (1) ◽

pp. 103-114 ◽

Cited By ~ 41

Author(s):

D Bellgrau ◽

D B Wilson

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Protective Immunity ◽

Specific Resistance ◽

T Cell Response ◽

F1 Hybrid ◽

Graft Versus Host ◽

Cell Immunity ◽

Alloreactive T Cell

The present studies extend our previous efforts to understand the immunological basis of specifically induced graft-versus-host (GVH) resistance in F1 hybrid rats. Immunization of F1 rats with alloreactive T-cell populations of parental strain origin induces a host-mediated T-cell response which is specific for anti-major hostocompatibility complex receptors on parental T cells. This protective immunity is rapid in onset and once induced, it provides a highly effective, specific resistance to lethal GVH disease which is radioresistant and can be adoptively transferred to syngeneic recipients.

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Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis

Scientific Reports ◽

10.1038/s41598-021-94483-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amanda W. K. AuYeung ◽

Robert C. Mould ◽

Ashley A. Stegelmeier ◽

Jacob P. van Vloten ◽

Khalil Karimi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vesicular Stomatitis Virus ◽

Cell Response ◽

Viral Infections ◽

T Cell Response ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Cell Immunity ◽

Vesicular Stomatitis

AbstractVaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.

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Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002269 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002269

Author(s):

Shota Aoyama ◽

Ryosuke Nakagawa ◽

Satoshi Nemoto ◽

Patricio Perez-Villarroel ◽

James J Mulé ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Tumor Growth ◽

Ex Vivo ◽

T Cell Response ◽

Effector Function ◽

Checkpoint Blockade ◽

Necrosis Factor Alpha ◽

Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

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Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

10.1101/2021.05.28.446009 ◽

2021 ◽

Author(s):

Antonella Scaglione ◽

Silvana Opp ◽

Alicia Hurtado ◽

Christine Pampeno ◽

Ziyan Lin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Protective Immunity ◽

T Cell Response ◽

Spike Protein ◽

Effector Memory ◽

World Population ◽

Vaccine Platform ◽

Vaccine Approach

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world population at record speeds. However, there is still demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (OX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T cell response in mice. Protein binding, immunohistochemical and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response that can be used as a new candidate to combat SARS-CoV-2. Given the strong T cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as, serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

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Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

Infection and Immunity ◽

10.1128/iai.00871-13 ◽

2013 ◽

Vol 81 (11) ◽

pp. 4171-4181 ◽

Cited By ~ 20

Author(s):

Laura A. Cooney ◽

Megha Gupta ◽

Sunil Thomas ◽

Sebastian Mikolajczak ◽

Kimberly Y. Choi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Inflammatory Cytokines ◽

Plasmodium Yoelii ◽

T Cell Response ◽

Parasite Development ◽

Effector Memory ◽

Cell Phenotype ◽

Effector Cells ◽

Ifn Γ

ABSTRACTVaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodentPlasmodium yoeliimodel. Protection is dependent on CD8+T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8+T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8+T cell phenotype and demonstrated significant upregulation of CD11c on CD3+CD8b+T cells in the liver, spleen, and peripheral blood. CD11c+CD8+T cells are predominantly CD11ahiCD44hiCD62L−, indicative of antigen-experienced effector cells. Followingin vitrorestimulation with malaria-infected hepatocytes, CD11c+CD8+T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c−CD8+T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8+T cells. Coculture of CD11c+, but not CD11c−, CD8+T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8+T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c+CD8+T cell response, but CD11c expression was lost as the CD8+T cells entered the memory phase. Further analyses showed that CD11c+CD8+T cells are primarily KLRG1+CD127−terminal effectors, whereas all KLRG1−CD127+memory precursor effector cells are CD11c−CD8+T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

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