Skin Delivery of Modified Vaccinia Ankara Viral Vectors Generates Superior T Cell Immunity Against a Respiratory Viral Challenge

AbstractModified Vaccinia Ankara (MVA) was recently approved as a Smallpox vaccine. Transmission of Variola is by respiratory droplets, and MVA delivered by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with VACV than any other route of delivery, and at much lower doses. Comparisons of s.s. with intradermal, subcutaneous or intramuscular routes showed that MVAOVA s.s.-generated T cells were both more abundant and transcriptionally distinct. MVAOVA s.s. produced greater numbers of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. compared to direct pulmonary immunization with MVAOVA, and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA. Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via direct pulmonary immunization. Overall, our data suggest that heterologous MVA vectors delivered via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens like COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine.

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Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge

npj Vaccines ◽

10.1038/s41541-020-00265-5 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Youdong Pan ◽

Luzheng Liu ◽

Tian Tian ◽

Jingxia Zhao ◽

Chang Ook Park ◽

...

Keyword(s):

T Cells ◽

Viral Vectors ◽

Effector T Cells ◽

T Cell Immunity ◽

Smallpox Vaccine ◽

Respiratory Pathogens ◽

Cell Immunity ◽

Respiratory Challenge ◽

Respiratory Droplets ◽

Route Of Delivery

AbstractModified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine. Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with vaccinia virus (VACV) than any other route of delivery, and at lower doses. Comparisons of s.s. with intradermal, subcutaneous, or intramuscular routes showed that MVAOVA s.s.-generated T cells were both more abundant and transcriptionally unique. MVAOVA s.s. produced greater numbers of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. immunization compared to intra-tracheal immunization with MVAOVA and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA. Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization. Overall, our data suggest that heterologous MVA vectors immunized via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens, which may be relevant to COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine.

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Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators

Blood ◽

10.1182/blood-2010-06-288498 ◽

2011 ◽

Vol 117 (7) ◽

pp. 2200-2210 ◽

Cited By ~ 69

Author(s):

Rikke Bæk Sørensen ◽

Sine Reker Hadrup ◽

Inge Marie Svane ◽

Mads Christian Hjortsø ◽

Per thor Straten ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Effector T Cells ◽

T Cell Immunity ◽

Regulatory Function ◽

Cytotoxic T Cell ◽

Interleukin 17 ◽

Patients With Cancer ◽

Indoleamine 2,3 Dioxygenase ◽

Cell Immunity

Abstract Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathologic settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in patients with cancer but also in healthy persons. We show that the presence of such IDO-specific CD8+ T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO+ suppressive cells. This had profound effects on the balance between interleukin-17 (IL-17)–producing CD4+ T cells and regulatory T cells. Furthermore, this caused an increase in the production of the proinflammatory cytokines IL-6 and tumor necrosis factor-α while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (ie, the TLR9 ligand cytosine-phosphate-guanosine, soluble cytotoxic T lymphocyte–associated antigen 4, or interferon γ) induced IDO-specific T cells among peripheral blood mononuclear cells from patients with cancer as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies in which IDO plays a significant regulatory role. We describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells “supporter T cells.”

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Programming Multifaceted Pulmonary T-Cell Immunity by Combination Adjuvants

10.1101/2020.07.10.197459 ◽

2020 ◽

Author(s):

Chandranaik B. Marinaik ◽

Brock Kingstad-Bakke ◽

Woojong Lee ◽

Masato Hatta ◽

Michelle Sonsalla ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Terminal Differentiation ◽

Influenza Viruses ◽

T Cell Immunity ◽

Effector Memory ◽

Respiratory Pathogens ◽

H5n1 Influenza ◽

Formidable Challenge ◽

Cell Immunity

AbstractInduction of protective mucosal T-cell memory remains a formidable challenge to vaccinologists. Using a novel adjuvant strategy that elicits unusually potent CD8 and CD4 T-cell responses, we have defined the tenets of vaccine-induced pulmonary T-cell immunity. An acrylic acid-based adjuvant (ADJ), in combination with TLR agonists glucopyranosyl lipid adjuvant (GLA) or CpG promoted mucosal imprinting but engaged distinct transcription programs to drive different degrees of terminal differentiation and disparate polarization of TH1/TC1/TH17/TC17 effector/memory T cells. Combination of ADJ with GLA, but not CpG, dampened TCR signaling, mitigated terminal differentiation of effectors and enhanced the development of CD4 and CD8 TRM that protected against H1N1 and H5N1 influenza viruses. Mechanistically, vaccine-elicited CD4 T cells played a vital role in optimal programming of CD8 TRM and anti-viral immunity. Taken together, these findings provide new insights into vaccine-induced multi-faceted mucosal T-cell immunity with significant implications in the development of vaccines against respiratory pathogens.One Sentence SummaryAdjuvants Induce Multipronged T-Cell Immunity in the Respiratory Tract.

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Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders

Blood ◽

10.1182/blood-2010-03-274076 ◽

2010 ◽

Vol 116 (13) ◽

pp. 2245-2252 ◽

Cited By ~ 37

Author(s):

Kimberley Jones ◽

Jamie P. Nourse ◽

Leanne Morrison ◽

Do Nguyen-Van ◽

Denis J. Moss ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Adoptive Immunotherapy ◽

Human Leukocyte ◽

Interferon Γ ◽

Effector T Cells ◽

T Cell Immunity ◽

Nuclear Antigen ◽

Post Transplantation ◽

Cell Immunity

AbstractImmunosuppression resulting in impaired Epstein-Barr virus (EBV)–specific T-cell immunity is involved in the pathogenesis of EBV-positive post-transplantation lymphoproliferative disorder (EBV+ PTLD). Restoration of EBV-specific T-cell immunity by adoptive immunotherapy can induce remission. EBV-nuclear antigen-1 (EBNA1) is unique in being expressed in all cases of EBV+ PTLD. Recent data demonstrate that EBNA1 is not immunologically silent and can be exploited as a T-cell target. There are no data on EBNA1-specific T cells in PTLD. EBNA1-specific T cells capable of proliferation, interferon-γ release, and CD107a/b degranulation were assayed in 14 EBV+ PTLD diagnostic blood samples and 19 healthy controls. EBNA1-specific CD4+ T cells predominated and were expanded in 10 of 14 patients and 19 of 19 controls. Although human leukocyte antigen class I alleles influenced the magnitude of the response, EBNA1-specific CD8+ effector T cells were successfully generated in 9 of 14 EBV+ PTLD patients and 16 of 19 controls. The majority of PTLD patients had a polymorphism in an EBNA1 epitope, and T-cell recognition was greatly enhanced when EBNA1 peptides derived from the polymorphic epitope were used. These results indicate that EBNA1-specific T cells should be included in adoptive immunotherapy for PTLD. Furthermore, expansion protocols should use antigenic sequences from relevant EBV strains.

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Ubiquitin specific protease 1 expression and function in T cell immunity

10.1101/2021.04.08.439046 ◽

2021 ◽

Author(s):

Kyla D Omilusik ◽

Marija S Nadjsombati ◽

Tomomi M Yoshida ◽

Laura A Shaw ◽

John Goulding ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Protein Level ◽

Cell Expansion ◽

T Cell Responses ◽

Effector T Cells ◽

Cell Responses ◽

Cell Immunity ◽

T Cell Expansion

AbstractT cells are essential mediators of the immune responses against infectious diseases and provide long-lived protection from reinfection. The differentiation of naive T cells to effector T cells and subsequent differentiation and persistence of memory T cell populations in response to infection is a highly regulated process. E protein transcription factors and their inhibitors, Id proteins, are important regulators of both CD4+ and CD8+ T cell responses; however, their regulation at the protein level has not been explored. Recently, the deubiquitinase USP1 was shown to stabilize Id2 and modulate cellular differentiation in osteosarcomas. Here, we investigated a role for Usp1 in posttranslational control of Id2 and Id3 in T cells. We show that Usp1 was upregulated in T cells following activation in vitro or following infection in vivo, and the extent of Usp1 expression correlated with the degree of T cell expansion. Usp1 directly interacted with Id2 and Id3 following T cell activation. However, Usp1-deficiency did not impact Id protein abundance in effector T cells or alter effector CD8+ T cell expansion or differentiation following a primary infection. Usp1 deficiency did result in a gradual loss of memory cells over time and impaired accumulation and altered differentiation following a secondary infection. Together, these results identify Usp1 as a player in modulating recall responses at the protein level and highlight differences in regulation of T cell responses between primary and subsequent infection encounters. Finally, our observations reveal that differential regulation of Id2/3 proteins between immune vs non-immune cell types.

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