Synergistic Role of TLR Agonists in T Cell-Mediated Immunity Induced by Mannose Receptor Antibody Targeting of Tumor Antigens to Human DCs

ABSTRACT The immune response to lymphocytic choriomeningitis virus in mice lacking macrophage inflammatory protein-1α (MIP-1α) was evaluated. Generation of virus-specific effector T cells is unimpaired in MIP-1α-deficient mice. Furthermore, MIP-1α is not required for T-cell-mediated virus control or virus-induced T-cell-dependent inflammation. Thus, MIP-1α is not mandatory for T-cell-mediated antiviral immunity.

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Monoclonal antibodies to LFA-1 and to CD4 inhibit the mixed leukocyte reaction after the antigen-dependent clustering of dendritic cells and T lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.165.5.1403 ◽

1987 ◽

Vol 165 (5) ◽

pp. 1403-1417 ◽

Cited By ~ 94

Author(s):

K Inaba ◽

R M Steinman

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cell Mediated Immunity ◽

Lymphocyte Function ◽

Mixed Leukocyte Reaction ◽

Binding Assays ◽

Lymphocyte Blastogenesis ◽

And Function

T cell proliferation in response to many stimuli is known to occur in discrete clusters of dendritic cells (DC) and CD4+ helper lymphocytes. The role of lymphocyte function-associated antigen (LFA-1) and CD4 in the formation and function of these clusters has been evaluated in the mixed leukocyte reaction (MLR). By day 1 of the control MLR, most of the DC and responsive T cells are associated in discrete aggregates. Addition of anti-LFA-1 and CD4 reagents does not block DC-T aggregation but reduces the subsequent proliferative response by 80-90%. Anti-LFA-1 disassembles newly formed DC-T cell aggregates, whereas anti-CD4 inhibits blastogenesis without disrupting the cluster. Binding of DC to sensitized, antigen-specific CD4+ cells has been studied using lymphoblasts isolated at day 4 of the MLR. It has been shown previously that greater than 80% blasts rebind to DC in an antigen-specific fashion in rapid (10 min) binding assays. Antigen-dependent DC-T binding is blocked by anti-Ia but not by mAb to LFA-1 or CD4. However, the bound anti-CD4-coated lymphocytes are unable to release IL-2. Anti-LFA-1-coated T cells release IL-2 but are easily disaggregated after binding to DC. These findings lead to two conclusions. LFA-1 and CD4 are not involved in the initial steps whereby DC bind to T cells but exert an independent and subsequent role. LFA-1 acts to stabilize the DC-T cluster, while CD4 contributes to lymphocyte blastogenesis and IL-2 release. Because DC but not other presenting cells cluster unprimed lymphocytes, it seems likely that an antigen-independent mechanism distinct from LFA-1 and CD4 mediates aggregate formation at the onset of cell-mediated immunity.

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The role of the T-cell receptor in thymocyte maturation: effects in vivo of anti-receptor antibody.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.83.22.8728 ◽

1986 ◽

Vol 83 (22) ◽

pp. 8728-8732 ◽

Cited By ~ 39

Author(s):

M. McDuffie ◽

W. Born ◽

P. Marrack ◽

J. Kappler

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Receptor Antibody

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Polymeric Pathogen-Like Particles-Based Combination Adjuvants Elicit Potent Mucosal T Cell Immunity to Influenza A Virus

Frontiers in Immunology ◽

10.3389/fimmu.2020.559382 ◽

2021 ◽

Vol 11 ◽

Author(s):

Brock Kingstad-Bakke ◽

Randall Toy ◽

Woojong Lee ◽

Pallab Pradhan ◽

Gabriela Vogel ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Influenza A ◽

Memory T Cells ◽

T Cell Immunity ◽

Cell Mediated Immunity ◽

Tlr Agonists ◽

Cell Immunity ◽

Resident Memory T Cells

Eliciting durable and protective T cell-mediated immunity in the respiratory mucosa remains a significant challenge. Polylactic-co-glycolic acid (PLGA)-based cationic pathogen-like particles (PLPs) loaded with TLR agonists mimic biophysical properties of microbes and hence, simulate pathogen-pattern recognition receptor interactions to safely and effectively stimulate innate immune responses. We generated micro particle PLPs loaded with TLR4 (glucopyranosyl lipid adjuvant, GLA) or TLR9 (CpG) agonists, and formulated them with and without a mucosal delivery enhancing carbomer-based nanoemulsion adjuvant (ADJ). These adjuvants delivered intranasally to mice elicited high numbers of influenza nucleoprotein (NP)-specific CD8+ and CD4+ effector and tissue-resident memory T cells (TRMs) in lungs and airways. PLPs delivering TLR4 versus TLR9 agonists drove phenotypically and functionally distinct populations of effector and memory T cells. While PLPs loaded with CpG or GLA provided immunity, combining the adjuvanticity of PLP-GLA and ADJ markedly enhanced the development of airway and lung TRMs and CD4 and CD8 T cell-dependent immunity to influenza virus. Further, balanced CD8 (Tc1/Tc17) and CD4 (Th1/Th17) recall responses were linked to effective influenza virus control. These studies provide mechanistic insights into vaccine-induced pulmonary T cell immunity and pave the way for the development of a universal influenza and SARS-CoV-2 vaccines.

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T-Cell-Mediated Immunity and the Role of TRAIL in Sepsis-Induced Immunosuppression

Critical Reviews in Immunology ◽

10.1615/critrevimmunol.2013006721 ◽

2013 ◽

Vol 33 (1) ◽

pp. 23-40 ◽

Cited By ~ 31

Author(s):

Stephanie A. Condotta ◽

Javier Cabrera-Perez ◽

Vladimir P. Badovinac ◽

Thomas S. Griffith

Keyword(s):

T Cell ◽

Cell Mediated Immunity

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1061The Role of CD4 T Cell Mediated Immunity in Pandemic Influenza Protection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofu052.769 ◽

2014 ◽

Vol 1 (suppl_1) ◽

pp. S311-S311

Author(s):

Jennifer Nayak ◽

Andrea Sant ◽

Shabnam Alam

Keyword(s):

T Cell ◽

Pandemic Influenza ◽

Cd4 T Cell ◽

Cell Mediated Immunity

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Role of the Mannose Receptor in a Murine Model of Cryptococcus neoformans Infection

Infection and Immunity ◽

10.1128/iai.00095-08 ◽

2008 ◽

Vol 76 (6) ◽

pp. 2362-2367 ◽

Cited By ~ 86

Author(s):

Jennifer M. Dan ◽

Ryan M. Kelly ◽

Chrono K. Lee ◽

Stuart M. Levitz

Keyword(s):

T Cell ◽

Cryptococcus Neoformans ◽

Cell Function ◽

Ex Vivo ◽

T Cell Responses ◽

Mannose Receptor ◽

Wild Type ◽

Cell Responses

ABSTRACT Cryptococcus neoformans is an encapsulated fungal pathogen with a predilection to infect persons with suppressed T-cell function. Cryptococcal mannoproteins (MP) are highly mannosylated antigens which elicit T-cell responses in infected mice and in convalescent patients. Key to the immunogenicity of MP is its capacity to bind to the conserved mannose receptor (MR), CD206, on dendritic cells (DCs). To test the role of the MR in the immune response to C. neoformans, wild-type and MR knockout (MR KO) mice were compared by using in vivo and ex vivo models of cryptococcosis. Following a pulmonary challenge with C. neoformans, MR KO mice died significantly faster than wild-type mice and had higher lung fungal burdens after 4 weeks of infection. Uptake of MP was similar when DCs obtained from wild-type and MR KO mice were compared. Additionally, MP did not upregulate the maturation markers major histocompatibility complex class II, CD86, and CD40 in either wild-type or MR KO DCs. However, MP stimulated lymphoproliferation in CD4+ T cells obtained from the peripheral lymph nodes of infected wild-type but not MR KO mice. These studies demonstrate a nonredundant role for the MR in the development of CD4+ T-cell responses to MP and protection from C. neoformans.

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R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming

Blood ◽

10.1182/blood-2011-05-357319 ◽

2012 ◽

Vol 119 (7) ◽

pp. 1693-1701 ◽

Cited By ~ 16

Author(s):

Gobind Singh ◽

Daigo Hashimoto ◽

Xiaocai Yan ◽

Julie Helft ◽

Patricia J.-Y. Park ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Dendritic Cell Maturation ◽

Cell Mediated Immunity ◽

G Protein Signaling ◽

Protein Signaling ◽

Cell Responses ◽

Small G Protein ◽

Physiologic Function

Abstract R-Ras is a member of the RAS superfamily of small GTP-binding proteins. The physiologic function of R-Ras has not been fully elucidated. We found that R-Ras is expressed by lymphoid and nonlymphoid tissues and drastically up-regulated when bone marrow progenitors are induced to differentiate into dendritic cells (DCs). To address the role of R-Ras in DC functions, we generated a R-Ras-deficient mouse strain. We found that tumors induced in Rras−/− mice formed with shorter latency and attained greater tumor volumes. This finding has prompted the investigation of a role for R-Ras in the immune system. Indeed, Rras−/− mice were impaired in their ability to prime allogeneic and antigen-specific T-cell responses. Rras−/− DCs expressed lower levels of surface MHC class II and CD86 in response to lipopolysaccharide compared with wild-type DCs. This was correlated with a reduced phosphorylation of p38 and Akt. Consistently, R-Ras–GTP level was increased within 10 minutes of lipopolysaccharide stimulation. Furthermore, Rras−/− DCs have attenuated capacity to spread on fibronectin and form stable immunologic synapses with T cells. Altogether, these findings provide the first demonstration of a role for R-Ras in cell-mediated immunity and further expand on the complexity of small G-protein signaling in DCs.

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