Scientists blunt the effects of natural killer cells to improve vaccine effectiveness

+T cells. C57BL/6 mice were infected with an adenoviral vector encoding the HBV genome and treated with anti-NK1.1 (⍺NK) or an isotype control antibody before therapeutic vaccination. Intrahepatic lymphocytes were collected 14 days after immunization. (A) Quantitative real-time PCR analysis of HBsAg mRNA extracted from the livers of infected mice. (B) Representative diagram of CD8+T cells isolated from the spleens of CD45.2 PD-1KO or CD45.1 wild-type (WT) mice transferred to a recipient of an opposite inbred mouse one day before therapeutic vaccination. Example of PD-1 expression and IFN productiony on transferred PD-1KO and WT CD8+ T cells. *, p<0.05; p-values ​​were determined by Kruskal-Wallis test (ANOVA) with post hoc test for multiple comparisons (n=5 mice per group; two experiments combined). Credit: Science Translational Medicine (2022). DOI: 10.1126/scitranslmed.abi4670″ width=”566″ height=”227″/>

PD-1 dependent NK cell regulation of CD8+T cells. C57BL/6 mice were infected with an adenoviral vector encoding the HBV genome and treated with anti-NK1.1 (⍺NK) or an isotype control antibody before therapeutic vaccination. Intrahepatic lymphocytes were collected 14 days after immunization. (A) Quantitative real-time PCR analysis of HBsAg mRNA extracted from the livers of infected mice. (B) Representative plot of CD8+T cells isolated from the spleens of CD45.2 PD-1KO or CD45.1 wild-type (WT) mice transferred to a recipient contralateral inbred mouse one day before therapeutic vaccination. Example of PD-1 and IFN expressionMr production on transferred PD-1KO and WT CD8+ T cells. *, pScience Translational Medicine (2022). DOI: 10.1126/scitranslmed.abi4670

Scientists have discovered that the body’s own natural killer cells can suppress the immune benefits of therapeutic vaccines, a problem that could affect vaccinations against chronic viral infections and cancer.

Indeed, the scientific literature is replete with examples of otherwise effective vaccines that sometimes turn out to be ineffective. Increasingly, the reasons point to an enemy within the body itself: a friend who turns into an enemy.

Scientists at University College London are investigating the conundrum and turned to an animal model to decipher how natural killer cells inadvertently blunt the benefits of vaccines.

in Scientific Translational Medicine, Mariana O. Diniz, PhD, and colleagues report that natural killer cells can respond so strongly after vaccination that they negatively affect a critical component of the immune response—CD8+ T cells. This vital population can be overtired and exhausted, Diniz and her collaborators found, a phenomenon that makes vaccination less effective.

“Therapeutic vaccines for chronic infections have reduced efficacy due to the presence of exhausted T cells and [an] an environment that limits vaccine responses,” Diniz wrote, noting that the problem invariably begins with the aggression of natural killer cells.

Working with a mouse model, Diniz and colleagues found that the combination treatment could boost robust immune responses after vaccination by acting on natural killer cells. The strategy, the team said, could eventually prove useful in the design and improvement of therapeutic vaccines for chronic viral infections and cancer.

“A better understanding of the mechanisms that regulate CD8+T cell responses to therapeutic vaccines is needed to develop approaches to improve vaccine efficacy for chronic viral infections and cancer,” Diniz and the UCL team say in the journal.

Part of their research involves gaining an intimate knowledge of natural killer cells themselves, a population whose name alone can conjure up powerful images of destruction.

Natural killer cells are produced in the bone marrow as well as elsewhere in the body. Also known simply as a natural killer or just plain old NK cell, this population is a type of white blood cell that contains granules – microscopic particles – with enzymes capable of killing tumor cells or cells infected with a virus.

Natural killer cells were originally thought to develop exclusively in the bone marrow, but relatively recent evidence in humans and mice suggests that these cells can also develop and mature in secondary lymphoid tissues, such as the tonsils, spleen, and lymph nodes.

Killer cells are a type of immune cell and are crucial components of the innate immune system, the body’s rapid response network. It is present at birth and the immune response that is first on the scene in case of infection or cancer. The innate system exists separately from the adaptive immune system, which emerges around 12 months of age. The adaptive system, also known as acquired immunity, consists of a set of specialized immune cells—T cells, B cells, and protein antibodies—that seek out and destroy foreign invaders.

While the innate immune system is known for its rapid response, the adaptive immune system is known for its recall and ability to attack threats more quickly in the future by relying on its memory of the same invaders from the past.

The aim of the UCL research is to turn natural killer cells from enemy to friend in chronic disease vaccination situations. The team’s investigation revealed that natural killers disrupted the response of T cells in mice to ChAdOx1-HBV, an experimental vaccine for chronic hepatitis B virus infection.

The scientists found that hepatitis B infection increased expression of the PD-L1 protein on the surface of natural killer cells in the liver, which in turn suppressed T cells that had been primed by the vaccine.

However, depletion of natural killer cells enhanced T cell responses in mice after vaccination. Alternatively, the researchers found they could turn natural killer cells into immunostimulatory helpers by administering an anti-PD-L1 antibody before vaccination, leading to even stronger hepatitis B virus-specific T-cell responses.

The team then applied a similar approach to cell samples from patients with chronic hepatitis B and found that the strategy could have benefits in humans as well.

“Our findings outline an immunotherapeutic combination that can enhance the response to therapeutic vaccination in chronic hepatitis B and highlight the broader importance of PD-L1-dependent regulation of T cells by cytokine-activated natural killer cells,” Diniz concluded.


Maximizing the effectiveness of therapeutic vaccines one step closer


More info:
Mariana O. Diniz et al, NK cells limit therapeutic vaccine-induced CD8 + T cell immunity in a PD-L1-dependent manner, Scientific Translational Medicine (2022). DOI: 10.1126/scitranslmed.abi4670

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