GII.P16-GII.2 Recombinant Norovirus VLPs Polarize Macrophages Into the M1 Phenotype for Th1 Immune Responses

Norovirus (NoV) is a zoonotic virus that causes diarrhea in humans and animals. Outbreaks in nosocomial settings occur annually worldwide, endangering public health and causing serious social and economic burdens. The latter quarter of 2016 witnessed the emergence of the GII.P16-GII.2 recombinant norovirus throughout Asia. This genotype exhibits strong infectivity and replication characteristics, proposing its potential to initiate a pandemic. There is no vaccine against GII.P16-GII.2 recombinant norovirus, so it is necessary to design a preventive vaccine. In this study, GII.P16-GII.2 type norovirus virus-like particles (VLPs) were constructed using the baculovirus expression system and used to conduct immunizations in mice. After immunization of mice, mice were induced to produce memory T cells and specific antibodies, indicating that the VLPs induced specific cellular and humoral immune responses. Further experiments were then initiated to understand the underlying mechanisms involved in antigen presentation. Towards this, we established co-cultures between dendritic cells (DCs) or macrophages (Mø) and naïve CD4+T cells and simulated the antigen presentation process by incubation with VLPs. Thereafter, we detected changes in cell surface molecules, cytokines and related proteins. The results indicated that VLPs effectively promoted the phenotypic maturation of Mø but not DCs, as indicated by significant changes in the expression of MHC-II, costimulatory factors and related cytokines in Mø. Moreover, we found VLPs caused Mø to polarize to the M1 type and release inflammatory cytokines, thereby inducing naïve CD4+ T cells to perform Th1 immune responses. Therefore, this study reveals the mechanism of antigen presentation involving GII.P16-GII.2 recombinant norovirus VLPs, providing a theoretical basis for both understanding responses to norovirus infection as well as opportunities for vaccine development.

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CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response.

Journal of Experimental Medicine ◽

10.1084/jem.183.5.2129 ◽

1996 ◽

Vol 183 (5) ◽

pp. 2129-2142 ◽

Cited By ~ 211

Author(s):

P Borrow ◽

A Tishon ◽

S Lee ◽

J Xu ◽

I S Grewal ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Humoral Immunity ◽

Cd4 T Cells ◽

Antiviral Immunity ◽

Ctl Response ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Deficient Mice

The ligand for CD40 (CD40L) is expressed on the surface of activated CD4+ T cells and its role in T-B cell collaborations and thymus-dependent humoral immunity is well established. Recently, by generating CD40L-knockout mice, we have confirmed its previously described role in humoral immunity and defined another important function of this molecule in the in vivo clonal expansion of antigen-specific CD4+ T cells. Here, we investigated the potential in vivo role of CD40L in antiviral immunity by examining the immune response mounted by CD40L-deficient mice following infection with lymphocytic choriomeningitis virus (LCMV), Pichinde virus, or vesicular stomatitis virus. Humoral immune responses of CD40L-deficient mice to these viruses were severely compromised, although moderate titres of antiviral IgM and some IgG2a were produced by virus-infected CD40L-deficient mice by a CD4+ T cell-independent mechanism. By contrast, CD40L-deficient mice made strong primary CTL responses to all three viruses. Interestingly however, although memory CTL activity was detectable in CD40L-deficient mice two months after infection with LCMV, the memory CTL response was much less efficient than in wild-type mice. Together, the results show that CD40-CD40L interactions are required for strong antiviral humoral immune responses, and reveal a novel role for CD40L in the establishment and/or maintenance of CD8+ CTL memory.

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CD4+ T cells and IL-4-mediated support of Th1 immune responses

Trends in Immunology ◽

10.1016/s1471-4906(02)02220-2 ◽

2002 ◽

Vol 23 (6) ◽

pp. 280

Author(s):

Mark P Rubinstein ◽

David J Cole

Keyword(s):

T Cells ◽

Immune Responses ◽

Cd4 T Cells ◽

Th1 Immune Responses

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Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation

Frontiers in Immunology ◽

10.3389/fimmu.2021.636568 ◽

2021 ◽

Vol 12 ◽

Author(s):

Karthik Dhatchinamoorthy ◽

Jeff D. Colbert ◽

Kenneth L. Rock

Keyword(s):

T Cells ◽

Immune Responses ◽

Antigen Presentation ◽

Cd8 T Cells ◽

Class I ◽

Immune Control ◽

Class I Mhc ◽

Mhc I ◽

Mhc Class I Antigen ◽

Underlying Mechanisms

Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.

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